Arch. Pharm. Res.
(2021) 44:63–83
https://doi.org/10.1007/s12272-021-01306-w
REVIEW
Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes
Yeo‑Jung Kwon1 · Sangyun Shin1 · Young‑Jin Chun1 
Received: 16 October 2020 / Accepted: 6 January 2021 / Published online: 23 January 2021
© The Pharmaceutical Society of Korea 2021
Abstract  Human cytochrome P450 enzymes (CYPs) play
a critical role in various biological processes and human dis-
eases. CYP1 family members, including CYP1A1, CYP1A2,
and CYP1B1, are induced by aryl hydrocarbon receptors
(AhRs). The binding of ligands such as polycyclic aromatic
hydrocarbons activates the AhRs, which are involved in the
metabolism (including oxidation) of various endogenous
or exogenous substrates. The ligands that induce CYP1
expression are reported to be carcinogenic xenobiotics.
Hence, CYP1 enzymes are correlated with the pathogen-
esis of cancers. Various endogenous substrates are involved
in the metabolism of steroid hormones, eicosanoids, and
other biological molecules that mediate the pathogenesis
of several human diseases. Additionally, CYP1s metabolize
and activate/inactivate therapeutic drugs, especially, anti-
cancer agents. As the metabolism of drugs determines their
therapeutic efficacy, CYP1s can determine the susceptibility
of patients to some drugs. Thus, understanding the role of
CYP1s in diseases and establishing novel and efficient thera-
peutic strategies based on CYP1s have piqued the interest of
the scientific community.
Keywords  Cytochrome P450 (CYP) 1 enzymes ·
Polymorphism · Metabolic diseases · Cancer · Drug
metabolism
* Young‑Jin Chun
yjchun@cau.ac.kr
1
College of Pharmacy, Chung-Ang University, Seoul 06974,
Republic of Korea
Online ISSN 1976-3786
Print ISSN 0253-6269
Introduction
Several critical enzymes have an important role in cellular
metabolism under disease conditions or drug metabolism.
Hence, these enzymes and enzyme-related molecular mecha-
nisms can be a potential therapeutic target for human dis-
eases without a known cure. Previous studies have investi-
gated the potential of various enzymes as a therapeutic target
(Winkler et al. 2018). Cytochrome P450 enzymes (P450s or
CYPs) have been widely studied since their identification as
they are involved in the metabolism of various substrates,
including therapeutic agents and components of the biologi-
cal processes, in humans (Nebert et al. 2013; Rendic and
Guengerich 2015). In particular, more than 95% of oxidative
and reductive reactions are reported to be catalyzed by CYPs
(Rendic and Guengerich 2015).
CYPs are a unique family of heme proteins containing
ferrous ion ­(Fe2+) and function as oxygenases in mono-
oxidation or mixed-function oxidation reactions (Denisov
et al. 2005; Julsing et al. 2008; Guengerich 2018) (Fig. 1).
Most organisms are reported to express CYPs. Addition-
ally, more than 10,000 sequences of CYPs have been identi-
fied with 57 CYP genes reported in humans (Nelson 2009;
Durairaj et al. 2019). Human CYP genes, which are classi-
fied into 18 families and 43 subfamilies (Elfaki et al. 2018),
mediate the activation/inactivation of exogenous substrates,
including drugs, foreign chemicals, food additives, or endog-
enous compounds, such as steroids, eicosanoids, or fatty
acids (Guengerich 2005; Nebert and Dalton 2006). Of the
18 families, only four families (CYP1, CYP2, CYP3, and
CYP4) are encoded by redundant genes, which are inducible
by various stimuli, such as environmental chemicals. The
members belonging to the remaining 14 families, which are
not inducible, are reported to be directly involved in essential
cellular functions (Nebert and Gonzalez 1987; Nebert 1991;
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64 Y.-J. Kwon et al.

Fig. 1  General function of
CYPs as oxygenases. a General
oxidase stoichiometry of CYPs
(Guengerich 2003). R stands
for substrate and RO represents
enzyme product of CYPs.
Substrates for CYPs are drugs,
procarcinogens, steroids, etc.
b Scheme of general cata-
lytic cycle for CYP reactions
(Guengerich 2018). Between
steps 4 and 8, the electronic
distribution in the Fe–O entities
has not been fully elucidated
yet in most of cases. In cases
of some CYPs like bacterial
and mitochondrial CYPs, the
electronic donations from ferre-
doxin proteins are associated
with steps 2 and 4

Nelson et al. 2004). The common metabolic substrates of
these 4 CYP families are drugs, xenobiotics, and eicosa-
noids, including prostaglandins and leukotrienes, which are
involved in various biological processes (Capdevila et al.
2002; Nebert and Dalton 2006). Hence, these four CYP
families are reported to be associated with the pathogenesis
of some human diseases. In contrast to the other three fami-
lies that comprise large numbers of CYPs, the CYP1 fam-
ily comprises only three members (CYP1A1, CYP1A2, and
CYP1B1) (Nelson et al. 2004) (Table 1). Additionally, the
expression of CYP1 family members is induced by chemi-
cal stimuli, such as ligands of the aryl hydrocarbon receptor
(AhR), including polycyclic aromatic hydrocarbons (PAHs)
and dioxins (Ibrahim et al. 2020; Perepechaeva et al. 2020).
The CYP1 family members are involved in various biologi-
cal processes (Gassmann et al. 2010; Nebert et al. 2013)
(Table 2).
CYP1 family members are involved in the metabo-
lism of estrogen ­(E 2 , 17β-estradiol) (Yamazaki et  al.
1998). Several CYPs, including CYP1, catalyze the
NADPH-dependent oxidation of estrogen, which results
in the production of hydroxylated estrogen metabolites
(Zhu and Conney 1998). The type of metabolite gener-
ated is dependent on the position of oxidation catalyzed
by CYP1 enzymes, which catalyze the major oxidative
pathways through 2-, 4-, and 16α-hydroxylation (Aoyama

Table 1  Substrates and related human diseases of CYP1, 2, 3, and 4

CYP family Number Substrates Previously reported diseases or properties in correla-
of genes tion with CYPs

CYP1 3 Eicosanoids, xenobiotics, drugs, foreign chemicals, sex steroids
+Melatonin, oestrogen, uroporphyrin (1A2)
CYP2 16 Eicosanoids, xenobiotics, drugs, foreign chemicals
+Nitrosamine (2A7), vitamin D 25-hydroxylation (2R1), reti-
noids (2S1), long-chain fatty acids (2U1)
CYP3 4 Eicosanoids, xenobiotics, drugs, foreign chemicals, sex steroids
CYP4 12 Eicosanoids, xenobiotics, drugs, foreign chemicals
+Anandamide in brain (4X1), fatty acid (4Z1)
Primary congenital glaucoma (buphthalmos),
Inflammatory disease, cancer
Vitamin D 25-hydroxylase deficiency
Metabolizes more than 60 % of clinically used drugs
Association with hypertension, coronary artery disease

In human CYP families, only 4 families, CYP1-4, are often redundant and induced by chemical and environmental stimuli. The members of
CYP1-4 families participate in the metabolism of various substrates and are extensively involved in metabolic human disease as summarized in
this table (Guengerich 2003; Nebert and Dalton 2006; Nebert et al. 2013)

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Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes 65

Table 2  Detectable locations CYP1s Detectable tissues Localization Major substrate Typical reaction
and typical reactions for major area in cells for major sub-
substrates of CYP1s strate

CYP1A1 Extrahepatic sites (lungs, Endoplasmic Benzo[α]pyrene 3-hydroxylation

kidney, brain, etc.) and reticulum
peripheral blood cells (ER)
CYP1A2 Liver (exclusive) ER Caffeine N3-demethylation
CYP1B1 Extrahepatic sites (brain, ER 17β-estradiol ­(E2) 4-hydroxylation
breast, colon, lung, kidney,
ovary, prostate, etc.)

CYP1A1 and 1B1 are extrahepatic CYPs while CYP1A2 exclusively exists in liver as hepatic CYP. CYP1s
are detected to be localized in endoplasmic reticulum (ER) of cells and responsible for various metabolic
processes for exogenous and endogenous substrates. Among them, the major substrates and typical reac-
tions for major substrates are elucidated in this table (Guengerich 2005)

et  al. 1990; Hayes et  al. 1996; Zhu and Conney 1998) metabolizes ­E2 through 2-hydroxylation. The CYP1A2-
(Fig. 2; Table 3). CYP1A2, a major hepatic CYP that is catalyzed 2-hydroxyestradiol synthesis and the CYP3A4-
exclusively expressed in the liver along with CYP3A4, catalyzed 16α-hydroxylation may be the major hepatic

Fig. 2  Estrogen metabolism by CYP1s (Zhu and Conney 1998). a 17β-estradiol ­(E2), a major substrate for CYP1-mediated hydroxylation.
CYP1s induce hydroxylation of E ­ 2 mainly on C-2 and C-4. Additionally, CYP1A2 also mediates the hydroxylation on C-16 (16α-hydroxylation)
in liver but the major role of CYP1A2 in estrogen metabolism is a hydroxylase for C-2 site. b Scheme for E ­ 2 metabolism which is initiated by
CYP1s. CYP1A1 and 1A2 mainly induce hydroxylation of E ­ 2 on C-2 and generates 2-hydroxyestradiol (2-OHE2) while the major metabolite of
CYP1B1 is 4-hydroxyestradiol (4-OHE2) through hydroxylation on C-4 of ­E2. 2- and 4-OHE2 are converted into quinone conjugates and conse-
quently induce genetic mutation via induction of DNA adducts

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66 Y.-J. Kwon et al.

Table 3  Positions of hydroxylation of ­E2 and products from metabolism on different positions

Position of hydroxylation on Mainly responsible CYP1 enzyme Estrogen metabolites generated from CYP1-induced hydroxylation
17β-estradiol ­(E2) for hydroxylation
Systemic name Common name

C-2 CYP1A1, CYP1A2 1,3,5(10)-Estratrien-2,3,17β-triol 2-Hydroxyestradiol

C-4 CYP1B1 1,3,5(10)-Estratrien-3,4,17β-triol 4-Hydroxyestradiol
C-16 CYP1A2 (liver) 1,3,5(10)-Estratrien-3,16α,17β-triol 16α-Hydroxyestradiol

The major role of CYP1s is a hydroxylase for E ­ 2. Each CYP1 shows preference for certain positions of E ­ 2 to induce hydroxylation. Different
metabolites are generated in regards of hydroxylated positions as described in this table (Zhu and Conney 1998; Badawi et al. 2001)

pathways of ­E2 metabolism (Yamazaki et al. 1998; Badawi
et al. 2001). The 4-hydroxylation activity of extrahepatic
CYP1B1 is markedly higher than the other catalytic activ-
ity of CYP1B1 for estrogen metabolism whereas hepatic
CYP1A2 and the other extrahepatic CYP1, CYP1A1,
much prefer to hydroxylate the ­E2 on C-2 rather than on
C-4. Additionally, previous studies have demonstrated that
the formation of 4-hydroxyestradiol is the unique cata-
lytic function of CYP1B1 in humans (Badawi et al. 2001;
Nishida et al. 2013). The main metabolites of CYP1-cat-
alyzed reactions, 2- or 4-hydroxyestradiol (2-, 4-OHE 2),
play a critical role in signaling pathways through the for-
mation of DNA adducts or glutathione conjugates, which
mediate the pathogenesis of human diseases by promoting
DNA damage (Dawling et al. 2004; Belous et al. 2007).
Previous studies have reported that in addition to the
CYP2, 3, and 4 family members, the CYP1 family mem-
bers exhibit polymorphisms with differential enzyme
activities, which result in the formation of various metabo-
lites (Nebert and Dalton 2006). At least 12, 33, and 24 var-
iant alleles have been reported for CYP1A1, CYP1A2, and
CYP1B1, respectively. These variants are responsible for
disease induction or susceptibility to chemicals and drugs
(Sarfarazi and Stoilov 2000; Nebert et al. 2004; Nebert
and Dalton 2006) (Table 4). Hence, previous studies have
investigated the biological functions of different CYP1
variants to examine the correlation between gene poly-
morphisms and biological activity. In this review, recent
discoveries on CYP1 genes will be discussed, especially
those related to the correlation between human disease and
genetic polymorphism along with the underlying molecu-
lar mechanisms.
CYP1A1
Clinical and experimental evidence of the role
of CYP1A1 in various diseases
CYP1A1 is reported to be involved in the pathogenesis of
lung cancer. CYP1A1 encodes aryl hydrocarbon hydroxy-
lase (AHH) or benzo[α]pyrene (B[α]P) hydroxylase, which
metabolizes PAHs in tobacco smoke (IARC 1987; Nebert
et al. 2004). Patients with lung cancer exhibit enhanced
expression of CYP1A1 in the bronchial mucosa. As the
induction of AHH expression is a risk factor for human lung
cancer, CYP1A1 is considered as a representative biomarker
for lung cancer (McLemore et al. 1990; Kawajiri et al. 1993).
CYP1A1 is expressed in the extrahepatic tissues and upregu-
lated in the tumor tissues. Hence, CYP1A1 is reported to be
associated with increased susceptibility to the development
of cancers in various regions (Hukkanen et al. 2002; Slattery
et al. 2004; Zhang et al. 2004; Androutsopoulos et al. 2009).
Recent studies have reported the role of CYP1A1 in the
pathogenesis of inflammatory diseases as it functions as an
oxygenase in eicosanoid metabolism. CYP1A1 induces oxi-
dative injury in the cells or tissues through the activation
of reactive oxygen species (ROS) production (Zhang et al.
2013a, b; Hussain et al. 2014; Zhou et al. 2017; Yuan et al.
2019). However, other studies have reported that CYP1A1
protects lung tissues against injury from oxidative damage

Table 4  Polymorphisms of CYP1s. CYP1s have several polymorphic alleles with different level of catalytic activity
CYP1 enzyme Number of identified Specific properties related to polymorphic variants
variants

CYP1A1 12 Non of these variants exhibit the altered activity for PAH metabolism
CYP1A2 33 There are >60-fold variabilities in hepatic basal CYP1A2 activity between individuals
CYP1B1 24 Mostly located in exon II and III with missense mutations or truncating mutations

The polymorphisms of CYP1s are extensively associated with inducibility and severity of CYP1-related human diseases. The number of variants
which are identified to date and the specific properties of each CYP1 in perspective of polymorphism are demonstrated in this table (Sarfarazi
and Stoilov 2000; Nebert et al. 2004)

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Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes 67
(Lingappan et al. 2014; Maturu et al. 2017). Furthermore,
the expression of CYP1A1 in the organs, including the liver,
kidney, and brain, is upregulated under certain conditions
but downregulated in response to inflammatory stimuli
(Morgan 2001; Santes-Palacios et  al. 2016). In patients
with sepsis, CYP1A1 is upregulated and promotes immune
responses through the upregulation of 12S-hydroxy-5Z, 8Z,
10E, 14Z-eicosatetraenoic acid production and the activa-
tion of JNK-AP1 signaling (Tian et al. 2020a, b). However,
CYP1A1 alleviates the inflammatory response through
the regulation of the NF-κB signaling pathway in a bovine
mastitis model and suppresses the production of immune
cytokines in the mycoplasmal pneumonia model (Fang
et al. 2016; Zhang et al. 2018a, b). Moreover, the deficiency
of CYP1A1 exacerbates the acute lung injury caused by
lipopolysaccharide (LPS) in septic animal models through
activation of NF-κB signaling pathway (Tian et al. 2020a,
b). These contradictory findings suggest that the function
of CYP1A1 in inflammatory disease may depend on animal
species, tissue types, or cell types.
12 allelic variants of CYP1A1 have been identified, none
of which showed different levels of B[α]P hydroxylase activ-
ity (Nebert et al. 2004). Several single nucleotide polymor-
phisms (SNPs) of CYP1A1 have been widely investigated in
relation to human diseases such as cancers, oxidative stress-
related illness, or immune disorders. The most-studied and
common SNPs of CYP1A1 are MspI (rs4646903, 3798 T > C,
m1 polymorphism), Ile462Val (rs1048943, 2455A > G, m2
polymorphism), and Thr461Asn (rs1799814, 2453C > A, m4
polymorphism) (Ezzeldin et al. 2017). Recent studies have
suggested that m1 polymorphism may contribute to endome-
triosis, polycystic ovarian syndrome, ulcerative colitis, and
male infertility (Fan et al. 2016; Cao et al. 2019; Sen and
Stark 2019; Bayoumy et al. 2020; Mear et al. 2020). M1 and
m2 polymorphisms are considered as risk factors for cervi-
cal squamous cell carcinoma (CSCC) because they elevate
the susceptibility of human papilloma virus (HPV) 16/18
infection (Nath et al. 2020). M2 polymorphism has been
reported to intensify the aggressive periodontitis and might
alter the platelet activity via increasing the inflammatory
responses (Wang et al. 2019). M2 and m4 polymorphisms
are significantly associated with onset of presbycusis as oxi-
dant stress gene polymorphisms (Manche et al. 2016). In a
recent study, m1 polymorphism also has been identified to
contribute to development and progression of presbycusis
(Karimian et al. 2020). M1, m2, and m4 polymorphisms
have been widely recognized to be involved in risk of diverse
cancers such as breast, cervical, colorectal, larynx, lung, and
prostate cancers (Zheng et al. 2012; Ding et al. 2018; Naif
et al. 2018; Hoidy et al. 2019; Lu et al. 2020; Sanchez-Siles
et al. 2020; Sengupta et al. 2020). These findings show that
the polymorphic status of CYP1A1 is deeply associated with
various human diseases.
Current functions of CYP1A1 in therapeutic strategies
for diseases
Metabolism and activation for prodrugs
The expression of CYP1A1 in some tumors is higher than
that in the non-tumorous tissues. Additionally, CYP1A1 is
involved in the metabolism of drugs. Hence, various stud-
ies have devised strategies to synthesize prodrugs that exert
cytotoxic effects against cancer cells after CYP1A1-medi-
ated activation (Mescher and Haarmann-Stemmann 2018).
The prodrug is naturally activated in the tumors that exhibit
an upregulated expression of CYP1A1. Thus, prodrugs
are more effective and safer than other anti-cancer agents.
Aminoflavone (5-amino-2,3-fluorophenyl)-6,8-difluoro-
7-methyl-4H-1-benzopyran-4-one; AF; NSC 686288), a
prodrug currently undergoing phase II clinical trials, is one
of the representative prodrugs that are metabolized and acti-
vated by CYP1A1. The mechanisms underlying the growth-
inhibiting effects of AF against malignant cells involve DNA
damage and apoptosis (Pobst and Ames 2006; McLean
et al. 2008). Dacarbazine and procarbazine, which are anti-
cancer alkylating prodrugs used for treating lymphoma,
melanoma, and soft-tissue sarcoma, are also activated by
CYP1A1 through N-dealkylation (Rodriguez-Antona and
Ingelman-Sundberg 2006; Lewis et al. 2011). Flutamide,
a prodrug used for treating prostate cancer, is activated
through hydroxylation by CYP1s, including CYP1A1.
Among the three CYP1s, CYP1A1 weakly metabolizes flu-
tamide (Singh et al. 2000; Rochat et al. 2001). CYP1A1
catalyzes the conversion of ICT2700, a novel prodrug, to a
duocarmycin-like molecule with a cyclopropane ring, which
exerts cytotoxic effect through DNA alkylation (Pors et al.
2011; Ortiz de Montellano 2013). Additionally, CYP1A1
metabolizes 2-aryl-benzothiazoles, including 2-(4-amino-
3-methylphenyl)-5-fluorobenzothiazole (5F 203) and
5-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole (GW610),
which results in the formation of DNA adducts and metabo-
lites with anti-cancer activity (Bradshaw and Westwell 2004;
Tan et al. 2011). These prodrugs can also be metabolized
and activated by other CYPs. The expression of CYP1A1
in the tumor is lower than that of other tumor-specific
CYPs, such as CYP1B1. However, some prodrugs, such
as AF, procarbazine, and ICT2700 are primarily activated
by CYP1A1. Hence, these CYP1A1-activated prodrugs
exhibit a highly selective and efficient growth-inhibiting
activity against tumors overexpressing CYP1A1. Recent
studies have also reported novel prodrugs that are activated
by CYP1A1. Although most novel prodrugs are anti-cancer
agents, various prodrugs for different diseases, including
trypanosomiasis, have also been reported (Ju et al. 2014;
Fortin et al. 2017; Khosroshahi et al. 2020). Since the meta-
bolic activation by CYP1A1 is essential for these prodrugs,
13

68
the phenotypic status of CYP1A1 in patient should be con-
sidered before choosing the prodrugs.
Molecular mechanism of CYP1A1
Similar to other CYP1 enzymes, CYP1A1 is activated after
the cognate ligand binds to AhR, which results in confor-
mational changes in AhR. This promotes the binding of the
AhR-AhR nuclear translocator (ARNT) complex to the XRE
sequence (5′-GCGTG-3′) in the enhancer region (Mescher
and Haarmann-Stemmann 2018). Novel factors and signal-
ing pathways involved in the CYP1A1 gene regulation have
been previously reported. Specificity protein 1 (Sp1) and p53
were reported to be novel cofactors for the AhR-mediated
CYP1A1 transcriptional activation. Although Sp1 and p53
are well-known transcription factors, recent studies have
reported that Sp1, which is recruited by AhR, interacts with
AhR to induce the expression of CYP1A1. Meanwhile, p53
binds to the p53 response element region in the CYP1A1
promoter region upon B[α]P treatment (Wohak et al. 2016;
Ye et al. 2019).
CYP1A1 is post-transcriptionally regulated by vari-
ous microRNAs (miRNAs). miRNAs are small non-cod-
ing RNAs that downregulate the target messenger RNAs
(mRNAs) by binding to their 3′-untranslated regions (3′-
UTRs) (Bushati and Cohen 2007). The expression of
CYP1A1 in the human cells and tissues is suppressed by
miR-150, miR-21-3p, miR-892a, and miR-125b-5p (Choi
et al. 2012; Sturchio et al. 2014; Burgess et al. 2015; Lo
et al. 2017). Additionally, the expression levels of miR-21,
miR-34a, miR-132, miR-132-3p, miR-148b, miR-200a, and
miR-200b were negatively correlated with those of CYP1A1
proteins (Rieger et al. 2013; Mescher and Haarmann-Stem-
mann 2018). In addition to these miRNAs, several miRNAs
can potentially bind to CYP1A1 mRNA. These findings may
contribute to establish the novel therapeutic strategies for
human diseases which are involved in CYP1A1.
Novel strategies for targeting CYP1A1
In humans, CYP1A1 is involved in the pathogenesis of vari-
ous diseases, including cancer. Hence, novel methods have
been suggested to selectively suppress CYP1A1 expression.
N-(4-butyl)-4-chloroethoxy-1,8-naphthalimide (NBCeN)
is a novel CYP1A1-specific fluorescent probe that is an iso-
form of 4-hydroxy-1,8-naphthalimide (HN) fluorophore
with high specificity for CYP1A1 (Dai et al. 2017). This
CYP1A1-specific probe enabled real-time biomonitoring of
CYP1A1 in the living cells and tissues along with the effi-
cient and rapid screening of CYP1A1 modulators. Hence,
CYP1A1-specific probes, including NBCeN, can be a pow-
erful experimental tool to reveal the role of CYP1A1 in liv-
ing organisms and identify efficient regulators of CYP1A1.
13
Y.-J. Kwon et al.
A recent study also demonstrated an in silico approach to
screen and identify efficient and novel inhibitors of CYP1A1
(Tahir et al. 2019). A ligand-based pharmacophore mod-
eling was performed to identify the potential inhibitors of
CYP1A1 from the literature. These inhibitors were ranked
based on the binding affinity to CYP1A1.
CYP1A1 induces carcinogenesis in several organs. There-
fore, there are ongoing efforts to establish a safe and effi-
cient strategy to suppress CYP1A1 expression in cancers. A
recent study reported a gene silencing method using nano-
medicine for human lung cancer cells (Zhang et al. 2019a,
b). CYP1A1 siRNA was introduced into both in vitro and
in vivo lung cancer models using cationic liposomes gen-
erated using lipid film-coated proliposome microparticles
(Zhang et al. 2019a, b). The RNAi delivery system reported
in this study can potentially modulate the expression of
CYP1A1 regulatory factors, including miRNAs and tran-
scription factors. Recent studies have been suggested that
phytochemicals like flavonoids have significant potential
to inhibit the genotoxic effects of metabolites which are
generated by enzyme activity of CYP1A1 (Rannug 2020;
Santes-Palacios et al. 2020). Further studies are needed to
specifically regulate CYP1A1 expression and consequently
alleviate human diseases.
CYP1A2
Clinical and experimental evidence of the role
of CYP1A2 in various diseases
CYP1A2 is exclusively expressed in the liver. Along with
CYP3A4, CYP1A2 is mainly responsible for the metabo-
lism of drugs, xenobiotics, and estrones in the human liver.
Environmental factors (including coffee consumption and
cigarette smoking) activate CYP1A2 through polymorphic
alterations or chemical stimuli (such as PAHs) within them
(Backman et  al. 2008; Amin et  al. 2012). In particular,
CYP1A2 metabolizes environmental xenobiotics, such as
aromatic and heterocyclic amines (HAs) and PAHs, which
are produced during the roasting or charbroiling process of
meat. The metabolites generated from the metabolic activa-
tion of HAs and PAHs exhibit mutagenic and carcinogenic
properties (Sachse et al. 2003). CYP1A2 is suggested as
a biomarker for cancer as it can metabolize and activate
procarcinogens. However, this suggestion has been hardly
accepted because the mRNA expression level of CYP1A2
is reported to be highly variable between individuals. Addi-
tionally, the activity or expression level of CYP1A2 is
downregulated in some human cancers. Furthermore, the
cytotoxicity of 2-OHE2, a major metabolite of CYP1A2-
catalyzed reaction, is lesser than that of 4-OHE2 because
it is further metabolized into 2-methoxyestradiol. Various
Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes 69
clinical studies have demonstrated the anti-cancer effects of
2-methoxyestradiol (Lakhani et al. 2003; Faber et al. 2005;
Mueck and Seeger 2010; Ren et al. 2016; Wuensch et al.
2019). Among the three human CYP1s, CYP1A2 exhibits
the highest ­E2 hydroxylation activity on C-2, which results in
the generation of 2-OHE2. This indicated that CYP1A2 has
the potential to exert anti-cancer effects (Hong et al. 2004).
Recently, the tumor-suppressive function of CYP1A2 has
been identified in lung adenocarcinoma and hepatocellular
carcinoma patients (Gastelum et al. 2020; Yu et al. 2020).
Therefore, CYP1A2 is one of the risk factors of cancers as
it metabolizes and activates procarcinogens but not always
able to be considered as cancer inducing factor. Thus,
CYP1A2 polymorphism is widely studied in various types
of cancers (He and Feng 2015; Koonrungsesomboon et al.
2018).
CYP1A2 is also associated with multiple non-tumorous
liver diseases as its expression is upregulated in the liver
(constituting approximately 15% of the hepatic levels of
CYPs) (Wang and Tompkins 2008). The expression and
activity of CYP1A2 are downregulated in patients with
non-alcoholic fatty liver disease (NAFLD), the most wide-
spread liver disease in United States and other nations
which has been recently recognized as a significant clini-
cal disorder, and in the animal model of NAFLD (Wieck-
owska and Feldstein 2008; Fisher et al. 2009; Merrell and
Cherrington 2011). NAFLD is characterized by non-alco-
holic steatohepatitis, steatosis, fibrosis, and cirrhosis in
the hepatic tissues and hepatocytes (Yoshioka et al. 2004;
Kleiner and Makhlouf 2016; Cobbina and Akhlaghi 2017).
During the pathological progression of NAFLD, steatosis
leads to increased inflammation and ROS-induced oxida-
tive stress in patients with NAFLD (Cobbina and Akhlaghi
2017). The expression of CYP1A2 is also downregulated
in patients with sepsis. Several studies have demonstrated
that the inhibition of CYP1A2 is associated with the induc-
tion of pro-inflammatory responses, which leads to tissue
damage (Crawford et al. 2004; Wu et al. 2006). Addition-
ally, CYP1A2 modulates inflammation by metabolizing
eicosanoids. CYP1A2 primarily metabolizes arachidonic
acid to distinct regioisomers of epoxyeicosatrienoic acids
(EETs), which exert anti-inflammatory effects. A recent
study has suggested that CYP1A2 may function as an anti-
inflammatory factor through the generation of 17, 18-epoxy-
eicosatetraenoic acid(EpETE), a novel anti-allergy and anti-
inflammatory lipid mediator (Zordoky and El-Kadi 2010;
Nagatake and Kunisawa 2019). These findings suggest that
CYP1A2 may be considered as an anti-inflammatory CYP
enzyme in humans.
NAFLD is associated with an increased risk of develop-
ing type 2 diabetes (T2D) and cardiovascular disease (CVD).
Hence, several studies have investigated the potential cor-
relation of CYP1A2 with these extrahepatic manifestations
of NAFLD (Anstee et al. 2013). The expression of CYP1A2
in an experimental animal model fed on a fructose-rich diet,
which is associated with increased prevalence of obesity in
humans, was lower than that in the control group. Treat-
ment with an anti-diabetic drug mitigated the downregulated
expression of CYP1A2 (Chang et al. 2014). Moreover, one
study examining the correlation of CYP1A2 genotype with
the risk of developing myocardial infarction (MI), a major
cause of CVD-induced death worldwide, revealed that the
polymorphic genotype of CYP1A2 with low inducibility
was associated with an elevated risk of MI (Cornelis et al.
2004). These findings suggest that CYP1A2 is involved in
the pathogenesis of T2D and CVD through substrate detoxi-
fication rather than substrate activation. A recent clinical
study revealed that the activity of CYP1A2 in the T2D group
was higher than that in the control group (Urry et al. 2016).
However, this study also considered the coffee intake pat-
tern and involved a small group of participants (n = 16).
Therefore, further clinical studies are needed to determine
the activity of CYP1A2 in patients with T2D.
Additionally, several studies have revealed the potential
correlation of CYP1A2 with non-hepatic human diseases.
CYP1A2 is reported to function as a neuroprotective enzyme
in Parkinson’s disease through the demethylation and detoxi-
fication of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP), a parkinsonism-inducing neurotoxin (Coleman
et al. 1996; Forsyth et al. 2000). Furthermore, chronic inter-
mittent hypoxia, a major characteristic of sleep apnea, sig-
nificantly inhibited the expression of CYP1A2 in an animal
model. This suggested that the impaired drug-metabolizing
activity of CYP1A2 must be considered before adjusting
the dosage of drugs for patients with sleep apnea (Zhang
et al. 2018a, b).
Devising therapeutic strategies based
on the drug‑metabolizing activity of CYP1A2
The major role of CYP1A2 in humans is catalyzing the
oxidative metabolism of up to 10% of clinically relevant
drugs (Klein et al. 2010). Although there are diverse drugs
that are metabolized by CYP1A2, some specific drugs are
predominantly metabolized by CYP1A2. The representa-
tive substrate of CYP1A2 is caffeine. CYP1A2 catalyzes
the demethylation of more than 95% of caffeine and gener-
ates various primary metabolites, including paraxanthine,
theophylline, and theobromine (Guest et al. 2018). These
metabolites have a higher affinity to adenosine receptors than
caffeine. Additionally, theophylline (dimethylxanthine) is
also mainly metabolized by CYP1A2 (eliminates 75% of
theophylline) (Fredholm 1995; Faber et al. 2005; Barnes
2013). The major metabolic pathways, including hydroxyla-
tion, N-deethylation, N-demethylation, and N-oxidation, of
the following drugs are primarily catalyzed by CYP1A2:
13

70
flutamide (an endocrine therapeutic agent for prostate can-
cer), lidocaine (a local anesthetic agent; minor pathway),
melatonin (metabolizes 90%; a neuro- and cardio-protective
anti-cancer agent), tacrine (metabolizes more than 90%;
reversible cholinesterase inhibitor to treat Alzheimer’s dis-
ease), triamterene (metabolizes almost 100%; a potassium-
sparing diuretic), tizanidine (a skeletal muscle relaxant),
zolmitriptan (a highly selective anti-migraine agent), and
clozapine and olanzapine (anti-psychiatric agents) (Fontana
et al. 1998; Wild et al. 1999; Ozono et al. 2002; Zullino
et al. 2002; Granfors et al. 2004; Orlando et al. 2004; Fuhr
et al. 2005; Ma et al. 2005). Furthermore, other drugs, such
as acetophenone and 3,4-methylenedioxymethampheta-
mine (MDMA, ecstasy) are also metabolized by CYP1A2
but have minimal or unclear clinical relevance (Faber et al.
2005; Asakawa et al. 2017; Vizeli et al. 2017). Various drugs
are metabolized and excreted through CYP1A2-mediated
activity. However, these drugs can be activated as prodrugs
for therapeutic activity. Anti-cancer agents, such as dac-
arbazine, tegafur, flutamide, and a popular non-steroidal
anti-inflammatory prodrug, nabumetone, are prodrugs that
are activated by CYP1A2 (Ortiz de Montellano 2013). The
catalytic activity of CYP1A2 affects the pharmacokinetics
of drugs, including non-renal elimination and bioavailability.
Hence, the catalytic activity of CYP1A2 is a critical fac-
tor that determines the optimal dosage of therapeutic agents
(Perera et al. 2013; Sychev et al. 2018; Ruan and de Leon
2020).
The inducibility and catalytic activity of CYP1A2 are
often determined based on genetic polymorphisms. In
particular, SNPs of CYP1A2 have been extensively stud-
ied and more than 40 SNPs have been identified (Aldrich
et al. 2009). Several SNPs, including − 163C > A, exhibit
enhanced catalytic activity. In contrast, some CYP1A2
SNPs, such as 186F > L, exhibit impaired catalytic activity
(Murayama et al. 2004; Djordjevic et al. 2008; Koonrung-
sesomboon et al. 2018). The close linkage disequilibrium
between the most common and extensively studied CYP1A2
polymorphisms (− 163C > A, − 729C > T, − 739 T > G, − 24
67delT, − 3113G > A, and − 3860G > A) results in the gen-
eration of various CYP1A2 haplotypes (Gunes and Dahl
2008). Compared with the wild-type CYP1A2*1A (rapid
metabolizer), CYP1A2*1F (rs762551, − 163A > C) exhibits
slower drug (mainly caffeine) metabolism (slow metabo-
lizer) (Guest et al. 2018). Individuals with CYP1A2*1F
(− 163A > C) are associated with an increased risk of devel-
oping various human diseases, including hypertension,
MI, stroke, prediabetes, amyotrophic lateral sclerosis, and
blepharospasm (Cornelis et al. 2006; Palatini et al. 2009,
2015; Mao et al. 2020; Siokas et al. 2020a, b). The enhanced
consumption of coffee and smoking may elevate the activ-
ity of CYP1A2 through the induction of SNPs exhibiting
upregulated enzyme activity. However, further studies are
13
Y.-J. Kwon et al.
needed to elucidate the function of CYP1A2 haplotypes and
identify the novel genotype of CYP1A2 in humans based
on the phenotypes of coffee intake and smoking (Sachse
et al. 1999; Djordjevic et al. 2010; Lesche et al. 2020). The
therapeutic drugs that are substrates of CYP1A2 must be
established after the identification of the CYP1A2 genotype
in patients.
Several suggestions have been proposed to establish
therapeutic strategies by devising novel methods for tar-
geting and regulating the expression of CYP1A2. A recent
study reported a newly designed and synthesized quinazo-
line-based inhibitor of CYP1A2 (Corral et al. 2020). The
quinazoline moiety was selected as the basal structure of a
novel inhibitor based on previous findings that reported the
specific affinity of quinazoline compounds for CYP1A2 with
inhibitory effect (Veith et al. 2009). The novel inhibitors
strongly inhibited CYP1A2 activity.
Previously identified regulators for CYP1A2 expression
on a molecular regulatory basis, such as transcription fac-
tors, epigenetic modulators, and miRNAs, are considered
as potential candidates to target for regulation of CYP1A2.
Recently, several studies have been reported to regulate
CYP1A2 via targeting Pregnane X receptor (PXR) and
constitutive androstane receptor (CAR), transcriptional
inducers for CYP1A2 (Yoshinari et al. 2010; Manda et al.
2017). Especially in hypoxia status which affects the drug
metabolism through changes in drug-metabolizing enzymes,
the synergistic induction of CYP1A2 by combination of
rifampicin, a PXR agonist, and (6-(4-chlorophenyl)-imidazo
(2,1-b) thiazole-5-carbaldehyde) (CITCO), a CAR agonist,
has been significantly repressed (Duan et al. 2020). Fur-
thermore, prolyl hydroxylase domain 2 (PHD2) inhibitors,
hypoxia-inducible factor-α (HIF-α) stabilizers which mimic
hypoxia, downregulate the expression of CYP1A2 along with
PXR and CAR (Takano et al. 2021). The epigenetic modula-
tors, such as histone deacetylase inhibitors, are also eligible
for regulatory tools targeting CYP1A2 because hypomethyla-
tion and histone acetylation of CYP1A2 has been reported
to elevate the expression of CYP1A2 mRNA (Jin and Ryu
2004; Miyajima et al. 2009). Since the interindividual vari-
ation of CYP1A2 with different drug-metabolizing activity
possibly depends on the allele-specific expression which is
affected by DNA methylation, the epigenetic regulation of
CYP1A2 may contribute to establishing the personalized
therapeutic strategies (Ghotbi et al. 2009). The pharmaco-
genetic studies based on the drug-metabolizing activity of
CYP1A2 also have been conducted to establish personalized
therapeutic strategies for each individual with a specific dis-
ease. Thus, several miRNAs that potentially target CYP1A2
and regulate its drug-metabolizing activity have been identi-
fied through in silico screening with multiple studies vali-
dating the in silico prediction (Swart and Dandara 2014;
Wei et al. 2018). Along with previously identified miRNAs
Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes 71
which have been demonstrated to post-transcriptionally reg-
ulate CYP1A2 mRNA, such as miR-122, miR-320, and miR-
132-5p, novel miRNAs with potential to target CYP1A2 can
be efficient small molecular tools for regulation of CYP1A2
(Chen et al. 2017; Gill et al. 2017; Wei et al. 2018). In the
future, efficient strategies for personalized treatment will be
established through CYP1A2 genotype analysis of patients
and subsequent modeling for suitable regulation of CYP1A2
activity.
CYP1B1
Clinical and experimental evidence of the role
of CYP1B1 in various diseases
Similar to CYP1A1, CYP1B1 is expressed in various extra-
hepatic regions, including the eye, heart, prostate, uterus,
and ovary (Gajjar et al. 2012; Faiq et al. 2014). The major
endogenous substrate of CYP1B1 is E ­ 2. However, CYP1B1
also metabolizes arachidonic acid, retinol, and melatonin
through hydroxylation or oxidation (Choudhary et al. 2004;
Ma et al. 2005). As CYP1B1 exhibits multifunctional activi-
ties in diverse metabolic pathways, it is reported to play criti-
cal roles in various human diseases. The role of CYP1B1 is
extensively investigated in glaucoma and cancers.
Glaucoma
Glaucoma, a heterogeneous disease, is one of the leading
causes of permanent loss of eyesight worldwide (Weisschuh
and Schiefer 2003). In addition to blindness, glaucoma is
associated with neurodegenerative features, such as reti-
nal ganglion cell death and degeneration of the optic nerve
(Gong et al. 2015). The elevated intraocular pressure (IOP)
is considered as a major risk factor for glaucoma (Vasiliou
and Gonzalez 2008). Glaucoma has been classified into sev-
eral categories based on specific criteria. The three major
categories of glaucoma are primary open-angle glaucoma
(POAG), primary congenital glaucoma (PCG), and primary
angle closure glaucoma (PACG) (Vasiliou and Gonzalez
2008). Increased IOP and glaucoma are associated with
multiple developmental disorders, including Peters’ anom-
aly (PA) and Rieger’s anomaly (RA), which are categorized
as anterior segment dysgenesis (ASD) (Gould and John
2002). Various mutations in CYP1B1, including missense
and nonsense mutations, deletions, insertions, duplications,
and silent mutations, have been identified in patients with
POAG, PA, RA, and PCG (Vasiliou and Gonzalez 2008).
The mutation status in CYP1B1 is reported to determine
the severity of the glaucoma phenotype (Melki et al. 2005).
In patients with POAG, CYP1B1 functions as a genetic
modifier of myocilin (MYOC), which is involved in the
pathogenesis of POAG (Vincent et al. 2002; Fan et al. 2006).
Genetic linkage analysis and mutation screening identified
that mutant CYP1B1 causes PCG (Sarfarazi 1997). PCG,
a rare type of glaucoma, is an autosomal recessive disor-
der with impaired penetrance and the most common type of
glaucoma in children (Do et al. 2016; Chouiter and Nadifi
2017). Although various PCG loci have been mapped by
genome-wide association studies and genome sequencing
technologies, only CYP1B1 has been recognized as the
major PCG causative factor (Alsubait et al. 2020). More than
150 PCG-associated CYP1B1 mutations have been identi-
fied. Wild-type and mutant model structures corresponding
to several PCG mutations were established and subjected to
molecular dynamic simulations to reveal the properties of
the mutant enzyme structures (Achary et al. 2006; Chouiter
and Nadifi 2017).
CYP1B1 mutants exhibit impaired or loss of catalytic
activity and/or reduced abundance in the PCG and POAG
phenotypes (Chavarria-Soley et al. 2008; Lopez-Garrido
et al. 2010). The similarity of haplotype backgrounds of
glaucoma-related CYP1B1 mutations in patients with POAG
and PACG has been described in a previous study, which
reported that the PACG phenotype may share common
properties, including reduced enzyme activity, with POAG
phenotype (Chakrabarti et al. 2007). Mutant CYP1B1 exhib-
its impaired E
­ 2 hydroxylation activity in patients with glau-
coma, which promotes the nuclear localization of estrogen
receptor alpha (ERα). This leads to the binding of ERα to the
putative estrogen response elements in the promoter region
of MYOC (Mookherjee et al. 2012). In the glaucoma phe-
notype, the CYP1B1-mediated metabolism of arachidonic
acid and the subsequent generation of 12(R)-hydroxyeico-
satetraenoic acid (12(R)-HETE), a corneal arachidonic acid
metabolite that can potentially inhibit the activity of N­ a +,
+
­K -ATPase, may be downregulated (Masferrer et al. 1990a,
b). The downregulation of 12(R)-HETE enhances corneal
clouding related to glaucoma through the regulation of ­Na+,
­K+-ATPase activity, which influences corneal susceptibility
to pressure-induced hydration and increases IOP (Masferrer
et al. 1990a, b; Vasiliou and Gonzalez 2008). Furthermore,
melatonin, a substrate of CYP1B1, is reported to exert vari-
ous biological effects associated with glaucoma in the eye,
including dopamine synthesis/release and ocular growth and
development (Dubocovich 1983; Doyle et al. 2002; Rada
and Wiechmann 2006). Other substrates of CYP1B1, such
as retinoids affect the expression of tyrosine hydroxylase,
which may act as a modifier for iridocorneal angle defects
through the production of dihydroxyphenylalanine, a product
of tyrosinase-catalyzed reaction (Libby et al. 2003; Doshi
et al. 2006). Melatonin and retinoids are not sufficiently
metabolized by mutant CYP1B1 with impaired activity,
which results in the biological phenotypes associated with
glaucoma in the eye.
13

72
Recently, the molecular mechanism of CYP1B1 in glau-
coma has been elucidated. The deletion of CYP1B1 is
associated with enhanced oxidative stress in the trabecular
meshwork and retinal vascular cells, which affects the tissue
integrity and function through the modulation of the produc-
tion of extracellular matrix (ECM) proteins (Falero-Perez
et al. 2018). In a recent study, the transcriptome profiles
of CYP1B1 + / + and CYP1B1−/− retinal astrocytes show
that CYP1B1 may control the functions of retinal astro-
cytes which are significant for neurovascular development
and integrity through regulation of genes involved in cell
adhesion and migration (Falero-Perez et al. 2020). Moreo-
ver, recent studies have also reported novel mutations in
CYP1B1 and their functional significance in the surgical
management of glaucoma (Afzal et al. 2019; Coelho et al.
2019; Khafagy et al. 2019). Further studies are needed to
elucidate the mechanisms of glaucoma and devise novel effi-
cient therapeutic strategies.
Cancer
The role of CYP1B1 in cancers has been examined in several
studies as it exhibits tumor-specific extrahepatic expression
patterns in various types of tissues, including the breast,
ovary, prostate, brain, and colon tissues (Murray et  al.
1997, 2001; D’Uva et al. 2018). CYP1B1, which exerts
tumorigenic effects through its catalytic activity, is one of
the activators of procarcinogens, such as PAHs. The activ-
ity of CYP1B1 generates carcinogenic metabolites, which
results in the production of DNA adducts and promotes
DNA damage. During the metabolism of procarcinogens,
the generation of ROS may be upregulated, which promotes
tumorigenesis (Moorthy et al. 2015; Alsubait et al. 2020).
In the estrogen metabolism pathway, CYP1B1 catalyzes
the hydroxylation of E ­ 2 primarily at the C-4 site, which
results in the production of 4-OHE2. The major metabo-
lite of CYP1B1, 4-OHE2 is a potential key mediator of the
carcinogenic activity of CYP1B1. In the canonical metabo-
lism, 4-OHE2 reacts with quinones and is converted into
­E2-3,4-Q, which predominantly forms depurinating DNA
adducts and consequently promotes tumorigenesis through
the induction of DNA damage or aberrant gene expression
(Dawling et al. 2004; Alsubait et al. 2020). A recent study
elucidated the carcinogenic mechanism of CYP1B1, which
involves the 4-OHE2-mediated induction of cancer cell pro-
liferation and invasion by the activation of Wnt/β-catenin
signaling and the epithelial-mesenchymal transition (EMT)
process through the upregulation of Sp1 (Kwon et al. 2016).
CYP1B1 has been reported to inhibit the cancer cell apop-
tosis by epigenetic regulation of death receptor 4 (DR4) via
controlling DNA-binding activity of Sp1 (Kwon et al. 2018).
Furthermore, the anti-apoptotic effect of 4-OHE2 in can-
cer involves the induction of the protein expression level of
13
Y.-J. Kwon et al.
X-linked inhibitor of apoptosis protein (XIAP) through the
activation of protein kinase Cε (PKCε), which phosphoryl-
ates XIAP and inhibits the ubiquitin–proteasome-mediated
degradation of XIAP (Baek et al. 2019).
The carcinogenic effects of CYP1B1 are mainly mediated
through its catalytic activity, which results in the genera-
tion of 4-OHE2. Hence, various studies have examined the
correlation between CYP1B1 polymorphisms associated
with ­E2 metabolism and cancers. The following four allelic
variants of CYP1B1 have been identified in various types
of cancers: intron 1–13 C > T, codon 449 T > C, Arg48Gly
(142C > G, R48G), Ala119Ser (355G > T, A119S), Leu-
432Val (4326C > G, L432V), and Asn453Ser (4390A > G,
N453S) (Gajjar et al. 2012). In particular, the polymor-
phisms in exon 2 and 3 regions (R48G and A119S on exon
2, L432V, and N453S on exon 3) markedly affect the cata-
lytic activity of CYP1B1 (Chang et al. 2003; Gajjar et al.
2012). These four polymorphic variants exhibit higher cata-
lytic activity than the wild-type allele. The R48G substitu-
tion occurs in the region involved in protein folding and
stability. This variant exhibits enhanced activity through
the upregulation of gene expression rather than regulat-
ing its enzymatic function (Chang et al. 2003; Zhang et al.
2013a, b). A119S, which is located in substrate recognition
site 1, may enhance catalytic activity through the regula-
tion of substrate binding (Gotoh 1992). N453S and L432V
exhibited enhanced catalytic activity because both alleles
encode the heme-binding domain, which is critical for its
catalytic activity. Unlike L432V, N453S also suppresses the
expression level of CYP1B1 through the induction of protein
degradation (Chang et al. 2003; Bandiera et al. 2005). Previ-
ous studies have reported that polymorphic CYP1B1 alleles
with enhanced catalytic activity are risk factors for cancers
(Watanabe et al. 2000; Ko et al. 2001; Tanaka et al. 2002;
Sasaki et al. 2003; Gu et al. 2018). Taken together, CYP1B1
is generally considered as a tumorigenic enzyme in humans.
New evidence of the role of CYP1B1 in various diseases
In addition to glaucoma and cancer, diverse metabolic dis-
eases, including obesity, hypertension, and renal dysfunction
are correlated with CYP1B1. This is because CYP1B1 is
involved in the metabolism of various endogenous substrates
(Li et al. 2017).
The expression of CYP1B1 is upregulated during the
differentiation of C3H10T1/2 cells into adipocytes (Zhang
et al. 1998). Furthermore, genetic analysis after CYP1B1
disruption revealed that CYP1B1 induces the expression of
stearoyl-CoA desaturase 1 (SCD1) and various genes stim-
ulated by peroxisome proliferator-activated receptor alpha
(PPARα) that are involved in energy homeostasis (Larsen
et al. 2015). Moreover, deficiency of CYP1B1 ameliorated
high-fat diet-induced obesity, learning and memory deficits,
Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes 73
and glucose tolerance through the inhibition of genes
involved in fatty acid transport and synthesis, such as CD36,
SCD1, and fatty acid synthase and the upregulation of genes
related to fatty acid oxidation, such as uncoupling protein
2(UCP2), carnitine palmitoyltransferase 1a(CPT1a), and
Nuclear factor-erythroid-2 related factor 2 (Nrf2) (Liu et al.
2015; Yang et al. 2019). These data suggest that CYP1B1
may affect adipogenesis and induce obesity.
The correlation of CYP1B1 with hypertension, a leading
cause of CVD, has also been reported (Yaghini et al. 2010;
Falbova et al. 2020). In angiotensin II (Ang II)-dependent
hypertension, CYP1B1 is involved in Ang II-induced pro-
liferation, migration, and protein synthesis in the vascu-
lar smooth muscle cells by metabolizing arachidonic acid
(Yaghini et  al. 2010). Recent studies demonstrated that
CYP1B1 modulates Ang II-induced hypertension through
the generation of 6β-hydroxytestosterone (6β-OHT) from
testosterone, which plays a critical role in the upregulation
of Ang II-induced vascular reactivity and causes hypertro-
phy, endothelial dysfunction, and elevation of oxygen radical
production (Anderson and Mazzoccoli 2019; Pingili et al.
2020). Intracerebroventricular 6β-OHT contributes to Ang
II-induced hypertension in the brain by increasing the mean
arterial pressure, ROS production, and neuroinflammation in
the paraventricular nucleus (Singh et al. 2020). Furthermore,
CYP1B1 also influences Ang II-independent hypertension
by inhibiting ROS production and activity of ERK1/2 and
p37 MAPK (Li et al. 2017).
The etiological agents for most diseases associated with
aberrant CYP1B1-mediated metabolism are products gen-
erated from the metabolism of eicosanoids, including ara-
chidonic acid. EET and HETE, which are metabolites of
CYP1B1-mediated arachidonic acid metabolism, have been
reported to suppress glomerular filtration through the regula-
tion of the vasoconstrictor response of endothelin-1 and Ang
II in the kidney or modulation of the ­Na+ transport in the
proximal tubule, which consequently induces renal dysfunc-
tion (Li et al. 2017). CYP1B1-mediated ROS generation also
leads to renal dysfunction (Jennings et al. 2012). Moreover,
a recent study demonstrated that CYP1B1 is upregulated by
indoxyl sulfate in the uremic toxins of patients with chronic
kidney disease and induces cardiac hypertrophy through
the generation of HETE, a metabolite from arachidonic
acid metabolism that mediates the pathophysiology of the
cardiovascular system (Zhang et al. 2020). As CYP1B1 has
diverse endogenous substrates, its role in human diseases
must be explored further.
Novel suggestions for establishing therapeutic strategies
based on CYP1B1
CYP1B1 is involved in the metabolism of several drugs
through hydroxylation. Various studies have examined
the catalytic activity of CYP1B1 on chemotherapeutic as
CYP1B1 is expressed predominantly in the tumors and
involved in carcinogenesis. CYP1B1 inhibits the cytotoxicity
of various chemotherapeutics, including cisplatin, paclitaxel,
docetaxel, flutamide, mitoxantrone, tamoxifen, doxorubicin,
and daunomycin (McFadyen et al. 2001; Rochat et al. 2001;
Xie et al. 2017). Clinical and pre-clinical studies have also
demonstrated that CYP1B1 inhibits the cytotoxicity of these
chemotherapeutic agents against tumors (Sissung et  al.
2008; Cui et al. 2015). Thus, tumors expressing upregulated
CYP1B1 expression are resistant to the cytotoxic effects of
chemotherapy. This phenomenon has been identified as one
of the drug resistance mechanisms.
Therefore, therapeutic strategies for cancers should be
established based on the expression level of CYP1B1 or the
status of CYP1B1 polymorphism in the target tissues. To
improve the efficacy of chemotherapeutics, various stud-
ies have identified the inhibitor of CYP1B1 to attenuate
CYP1B1-induced drug resistance and established the treat-
ment combination of anti-cancer drugs and CYP1B1 inhibi-
tors. Naturally occurring compounds, including flavonoids,
coumarins, stilbenes, and anthraquinones, and several syn-
thetic aromatic compounds, such as α-naphthoflavone, are
reported to inhibit the catalytic activity of CYP1B1 (Chun
and Kim 2003; Cui et al. 2015; Dutour and Poirier 2017).
Several CYP1B1 inhibitors, such as resveratrol, isorhamne-
tin, and kaempferol inhibit the expression of AhR and con-
sequently, suppress the expression of CYP1B1 (Chun et al.
2009; Alsubait et al. 2020). Furthermore, the anti-cancer
agents that competitively inhibit CYP1B1 may also be con-
sidered as CYP1B1 inhibitors (Rochat et al. 2001). Novel
CYP1B1 inhibitors, such as the synthetic pyridylchalcones
7 k (DMU2105) and 6j (DMU2139), have been used in
combination with cisplatin to treat cancers. Treatment with
these inhibitors increased the sensitivity and susceptibility
of cancer cells to cisplatin (Horley et al. 2017). Addition-
ally, various novel inhibitors of CYP1B1, like carvedilol
and quinazoline derivatives have been reported (Siddique
et al. 2017; Wang et al. 2020). The treatment combination of
chemotherapeutic agents and CYP1B1 inhibitors may result
in enhanced anti-cancer efficacy.
Several prodrugs have been developed for targeting tumors
overexpressing CYP1B1. These prodrugs must be activated
by CYP1B1 to exert cytotoxic effects. Hence, these prodrugs
are associated do not exert cytotoxic effects on the non-can-
cerous tissues. Additionally, the growth-inhibiting activity
of these prodrugs is highly specific against the tumor tis-
sues. CYP1B1 also metabolizes 3,4-methylenedioxy-3′,4′,5′-
trimethoxychalcone (DMU-135), a novel prodrug that is
highly specific for tumors. DMU-135, which is metabolized
by CYP1B1 within the tumor tissues, exerts anti-cancer
effects through its metabolite, DMU-117, a potent tyrosine
kinase inhibitor, without exerting cytotoxic effects on the
13

74 Y.-J. Kwon et al.

non-cancerous tissues (Sale et al. 2006). The anti-cancer mech- substrates (Fig. 3; Table 5). In particular, CYP1 enzymes
anism of AF, which is a substrate of CYP1B1, is similar to that play a critical role in human diseases because their substrates
of DMU-135 (Kuffel et al. 2002). In some cases, the CYP1B1 are exogenous chemicals or endogenous substances with
inhibitors exert synergistic effects by producing metabo- potential pathogenic properties. Genetic variants of CYP1
lites with anti-cancer properties after being metabolized by enzymes are risk factors for various diseases owing to their
CYP1B1. Resveratrol, which is a natural stilbene that inhibits altered catalytic activity. The possibility of CYP1s acting
CYP1B1, is metabolized by CYP1B1 resulting in the gen- as direct regulators without exhibiting catalytic activity on
eration of piceatannol. Piceatannol exerts anti-cancer effects proteins such as transcription factors or proteases has not
through the inhibition of tyrosine kinases (Fleming et al. 1995; been clarified; this must be explored in further studies.
Potter et al. 2002; Gajjar et al. 2012). These findings indi- Occasionally, CYP1 enzymes exert incompatible effects
cate that the anti-cancer efficacy can be improved through the on specific biological processes depending on the experi-
development of novel strategies involving CYP1B1 inhibitor mental conditions. This might be caused by the complexity
and CYP1B1-metabolized prodrugs. of the CYP1 activity on a broad spectrum of substrates and
Various studies have examined the molecular mechanism the presence of unknown functions or substrates. There are
underlying the regulation of CYP1B1 expression and devel- several polymorphic alleles of CYP1s whose functions or
oped novel methods for suppressing CYP1B1 expression substrates have not yet been identified. The unknown func-
in cancers. The expression of CYP1B1 can be upregulated tions of CYP1s may be involved in various types of human
in cancers through hypomethylation of the promoter region diseases. The identification of novel functions and substrates
of CYP1B1 or by targeting the CYP1B1 mRNA-specific of CYP1s will provide useful insights into the pathological
miRNAs, such as miR-27b-3p and miR-187-5p (Tokizane processes of human diseases.
et al. 2005; Tsuchiya et al. 2006; Mao et al. 2016; Liu et al. The drug-metabolizing activity of CYP1s must be con-
2020). Interleukin-6 (IL-6), a pro-inflammatory cytokine sidered to formulate therapeutic strategies for some diseases
and a key factor for local inflammation in the colon, is a
risk factor for colon cancer. CYP1B1 can be induced by IL-6
through epigenetic modulation of miR-27b expression (Patel
et al. 2014). Leptin, a key factor in obesity-related breast
cancer that influences the balance of ­E2 metabolism, was
recently demonstrated to upregulate CYP1B1 by binding to
the CYP1B1 promoter (Shouman et al. 2016).
Several studies have suggested novel anti-cancer drugs
that target and attenuate CYP1B1 inducers or new strate-
gies using endogenous (miRNAs) or synthetic inhibitors
of CYP1B1. IL-6 promotes the expression of CYP1B1
through the IL-6/JAK/STAT3 signaling pathway. Hence,
novel agents targeting IL-6, the IL-6 receptor, or JAK that
have been approved by the Food and Drug Administration
for clinical use may efficiently inhibit CYP1B1 expression
in cancers (Patel et al. 2014; Johnson et al. 2018). Further-
more, the direct introduction of miR-27b into cancer cells
synergistically enhanced the cytotoxic effects of doxorubicin
through the suppression of CYP1B1 (Mu et al. 2015). A new
delivery system of the CYP1B1 inhibitor α-naphthoflavone
using hyaluronic acid-modified cationic nanoparticles has
been suggested to overcome the CYP1B1-mediated drug
resistance of cancers (Zhang et al. 2019a, b). Currently,
there are ongoing efforts to develop therapeutic strategies
and efficient methods to overcome drug resistance. Fig. 3  Summary for the functions of CYP1s and human diseases
which are related with CYP1s. CYP1s are commonly induced by aryl
hydrocarbon receptor (AhR)-AhR nuclear translocator (ARNT) com-
plex following binding of ligands to AhR. Ligands for AhR are chem-
Future perspective ical inducers like polycyclic aromatic hydrocarbons and extensively
exist in multiple environmental factors such as cigarette smoking.
CYP1s mediate metabolic processes for drugs, procarcinogens, and
Human CYP enzymes are involved in the pathogenesis of various endogenous substrates like steroids and show deep correlation
several human diseases as they metabolize a broad range of with metabolic diseases, including obesity, hypertension, and cancer

13
Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes 75

Table 5  Drug-metabolizing CYP1 enzyme Representative substrate drugs Functions of drugs

substrates of CYP1s
CYP1A1 Aminoflavone Anti-cancer agent prodrug
Dacarbazine/Procarbazine Alkylating agent prodrug
Flutamide Endocrine anti-prostate cancer agent prodrug
ICT2700 Duocarmaycin-like alkylating agent prodrug
5F 203/GW610 DNA adduct-inducing agent prodrug
CYP1A2 Caffeine Stimulator for central nerve system
Theophylline Drug for respiratory diseases/caffeine metabolite
Flutamide Endocrine anti-prostate cancer agent
Lidocaine Local anesthetic agent
Melatonin Neuro/cardio-protective anti-cancer agent
Tacrine Reversible cholinesterase inhibitor
Triamterene Potassium-sparing diuretic
Tizanidine Skeletal muscle relaxant
Zolmitriptan Highly selective anti-migraine agent
Clozapine/Olanzapine Anti-psychiatric agent
Acetophenone Ingredient for synthesis of pharmaceuticals
3,4-methylenedioxymethampheta- Psychoactive drug
mine (MDMA, ecstasy)
CYP1B1 3,4-methylenedioxy-3′,4′,5′- Anti-cancer agent prodrug
trimethoxychalcone (DMU-135) Anti-cancer agent prodrug
Aminoflavone Anti-cancer natural product
Resveratrol

CYP1s metabolize numerous drugs for various types of human diseases. The substrate drugs of CYP1s are
activated or eliminated by CYP1-induced metabolizing action. The drugs which are known to be metabo-
lized by CYP1s as their substrates have been described in the manuscript and summarized in this table

as it directly affects the efficacy of drugs. In addition to
anti-cancer therapeutic agents, CYP1s may metabolize
therapeutic agents of various human diseases. The identi-
fication of the correlation between CYP1s and drugs will
aid in developing therapeutic strategies for various diseases
in the future.
Acknowledgements  This study was supported by the National
Research Foundation of Korea (NRF) funded by Korean government
(MSIP) (NRF-2015R1A5A1008958).
Compliance with ethical standards  ery GW, Levy D, Psaty BM, Gudnason V, Chakravarti A, Sulem
Conflict of interest  The authors declare that there are no competing
interests.
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