Expert Opinion on Drug Metabolism & Toxicology

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The role of cytochrome P450 (CYP) enzymes in

hyperoxic lung injury

Rachel Stading , Xanthi Couroucli , Krithika Lingappan & Bhagavatula

Moorthy

To cite this article: Rachel Stading , Xanthi Couroucli , Krithika Lingappan & Bhagavatula Moorthy
(2020): The role of cytochrome P450 (CYP) enzymes in hyperoxic lung injury, Expert Opinion on
Drug Metabolism & Toxicology, DOI: 10.1080/17425255.2021.1853705

To link to this article: https://doi.org/10.1080/17425255.2021.1853705

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Opinion on Drug Metabolism & Toxicology

DOI: 10.1080/17425255.2021.1853705
The role of cytochrome P450 (CYP) enzymes in hyperoxic lung injury
Rachel Stading1, Xanthi Couroucli1, Krithika Lingappan1, Bhagavatula Moorthy1*

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Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s
Hospital, Houston, TX

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*Corresponding author: Bhagavatula Moorthy, Texas Children’s Hospital, Neonatology Research
Program, Department of Pediatrics, Baylor College of Medicine, 1102 Bates Ave, FC 530.04
Houston, TX 77030, Email: bmoorthy@bcm.edu

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Abstract
Introduction: Hyperoxic lung injury is a condition that can occur in patients in need of supplemental

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oxygen, such as premature infants with bronchopulmonary dysplasia or adults with acute respiratory
distress syndrome. Cytochrome P450 (CYP) enzymes play critical roles in the metabolism of endogenous

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and exogenous compounds.
Areas covered: Through their complex pathways, some subfamilies of these enzymes may contribute to
or protect against hyperoxic lung injury. Oxidative stress from reactive oxygen species (ROS) production

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is most likely a major contributor of hyperoxic lung injury. CYP1A enzymes have been shown to protect
against hyperoxic lung injury while CYP1B enzymes seem to contribute to it. CYP2J2 enzymes help

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protect against hyperoxic lung injury by triggering EET production, thereby, increasing antioxidant
enzymes. The metabolism of arachidonic acid to ω-terminal hydroxyeicosatetraenoic acid (20-HETEs) by
CYP4A and CYP4F enzymes could impact hyperoxic lung injury via the vasodilating effects of 20-HETE.

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CYP2E1 and CYP2A enzymes may contribute to the oxidative stress in the lungs caused by ethanol- and
nicotine-metabolism, respectively.
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Expert opinion: Overall, the CYP enzymes, depending upon the isoform, play a contributory or
protective role in hyperoxic lung injury, and are, therefore, ideal candidates for developing drugs that
can treat oxygen-mediated lung injury.
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Keywords: CYP1A enzyme; CYP2A enzyme; CYP4A enzyme; CYP1B enzyme; CYP2E1 enzyme; CYP4F
enzyme; CYP2J2 enzyme; cytochrome P450 (CYP) enzymes; hyperoxic lung injury; oxidative stress
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Article highlights
• CYP1A enzymes located in both the lungs and liver protect against hyperoxic lung injury (HLI) by
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metabolizing oxidative stress-contributing lipid peroxide products

• CYP1B1 enzymes alter DNA pathways under hyperoxic conditions, contributing to DNA adduct
formation and lung injury
• CYP2E1 and CYP2A enzymes can contribute to HLI when chronic ethanol and nicotine metabolism,
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respectively, occur and high amounts of reactive oxygen species (ROS) are released
• CYP2J2 enzymes increase epoxyeicosatrienoic acid (EET) production, which reduces oxidative
stress and HLI through vascular tone regulation and stimulation of antioxidant enzyme
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production
• CYP4A and CYP4F enzymes may impact HLI from production of ω-terminal
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hydroxyeicosatetraenoic acids (20-HETEs) but require further research

1. Introduction
Hyperoxic lung injury (HLI) is common in patients who need supplemental oxygen due to underlying lung

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disease [1]. The excess oxygen can cause an increase in reactive oxygen species (ROS), leading to
oxidative stress, and eventually, hyperoxic lung injury [2-5]. In acute respiratory distress syndrome

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(ARDS) in adults or in premature infants, supplemental oxygen may contribute to ROS accumulation,
resulting in further lung damage [6-9]. In preterm infants, oxygen-mediated lung injury could lead to
bronchopulmonary dysplasia (BPD) [10, 11]. Currently, improvements in the medical treatment of BPD

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have yet to lower the disease incidence [12-14]. More effective treatment options are needed urgently
for the treatment of these hyperoxic lung injury-mediated diseases in adults and kids.

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CYP enzymes are a diverse and important group of enzymes that metabolize endo- and exogenous
molecules [15, 16]. These monooxygenases play crucial roles in drug and xenobiotic metabolism as a

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phase I oxidative enzyme [17]. Because of their oxidative nature, these enzymes have shown to
contribute to oxidative stress through the release of reactive oxygen species (ROS) during reaction
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uncoupling of their enzymatic cycle [18]. However, their variability in function, expression in many
organs, complicated reaction pathways, and surrounding endogenous molecules influence how these
enzymes either contribute to or protect from oxidative stress and hyperoxic lung injury. Even CYP
enzymes of the same family can have opposite impacts on disease pathology [19].
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Genetic polymorphisms in CYP enzymes add another layer of biological variability and response, and
many of the polymorphisms modulate susceptibility to diseases [20]. Differences in the enzymatic rate
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of reaction, may alter the production of ROS and disease pathogenesis [21]. Age, sex, ethnicity, etc. all
play a role in determining the incidence of these polymorphisms [22].
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The CYP enzymes discussed in this review as they are related to hyperoxic lung injury are CYP1A1/A2,
CYP1B1, CYP2A, CYP2E1, CYP2J2, CYP4A, and CYP4F enzymes. Figure 1 displays a comprehensive
overview of how these enzymes relate to HLI.
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2. Role of CYP enzymes in the protection against hyperoxic lung injury

Several CYP enzymes can affect hyperoxic lung injury by protecting against oxidative stress. Due to the
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redundancy and overlap of the involved metabolic pathways, CYP enzymes located in other parts of the
body, such as the liver, can decrease inflammation and disease pathology in the lungs. The following
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sections delve into the interplay of these enzymes, oxidative stress, and hyperoxic lung injury. Figure 2
summarizes the mechanism by which the enzymes protect against HLI.

2.1 CYP1A1/1A2
CYP1A enzymes metabolize polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic
amines/amides (HAAs) into epoxide hydrolase [23-27]. The CYP1A subfamily consists of two enzymes,
CYP1A1 and CYP1A2, which are expressed in different organs in the human body [28]. CYP1A1 enzymes
are found mainly in extrahepatic tissues, while CYP1A2 enzymes are found mainly in the liver [29]. Both,
however, are shown to have significant effects on hyperoxic lung injury. Initial studies of CYP1A enzymes
reported CYP inhibition led to a reduction in pulmonary injury in animal models and hypothesized that
the ROS, specifically H2O2, produced by CYP1A enzymes lead to oxidative stress and increased
pulmonary lung injury [30]. Our studies and the studies of other groups have found that CYP1A enzymes
contribute to the protection against hyperoxic lung injury [30-35].

Okamoto et. al. [32] determined that rats placed in a hyperoxic environment showed signs of CYP1A1
and 1A2 enzyme induction in the liver and lungs [32]. In our study, 3-methylcholanthrene (3-MC) was
used to induce transcription of CYP1A enzymes via the aryl hydrocarbon receptor (AHR) [36, 37]. After
hyperoxia treatment of >95% O2, increased pulmonary injury was found in Cyp1a1-/-, CYP1a2-/-, and Ahr-/-

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adult mice groups [38-40]. In another similar study, decreased hyperoxic lung injury was observed in
newborn and adult mice as well as adult rats when a different AhR ligand, β-napthflavone (BNF), was

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used to induce CYP1A enzymes [33-35]. Signs of oxidative damage, such as increased levels of lipid
peroxidation and DNA damage, were found in the Cyp1a1-/- and Cyp1a2-/- mice [39-41]. More research is
needed to understand the mechanism behind the protective role of CYP1A enzymes in hyperoxic lung

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injury.

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One possible mechanism that causes the protective role of CYP1A enzymes is through the metabolism of
F2-isoprostane PGF2-α [42]. CYP1A1 enzymes have been shown to decrease levels of the lipid
peroxidation products, F2-isoprostane PGF2-α and isofuran, which have been shown to contribute to

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lung injury due to increased oxidative stress [39]. In Cyp1a2-/- mice, metabolic clearance of F2-
isoprostane PGF2-α in the liver is diminished, leading to accumulation and increased systemic circulation
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of this compound [40]. This circulation could result in increased expression of pro-inflammatory
cytokines, causing increased lung injury [40]. With the presence of CYP1A2 enzymes, the lipid peroxide
products formed in the lungs would be detoxified by the hepatic enzymes, which would decrease the
cytokine load and, therefore, decrease inflammation.
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2.2 CYP2J2
CYP2J2 enzymes have a significant presence in cardiovascular tissue but are also found in many other
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major organs, including the lungs, kidney, liver, pancreas, and intestines [43]. These enzymes play a
crucial role in metabolizing AA to epoxyeicosatrienoic acids (EETs) [43, 44]. EETs have been shown to
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regulate smooth muscle tone of pulmonary bronchi and vascular pulmonary tone [45]. EETs also are
important in decreasing ROS production and reducing oxidative stress by inhibiting Bach-1, which is a
negative feedback regulator of the antioxidant enzyme HO-1 [46]. The inhibition of Bach-1 results in
increased expression of HO-1, which reduces oxidative stress and inflammation. Studies have also
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shown that inhibition of soluble epoxide hydrolase (sEH), a metabolizer of EETs to

dihydroxyeicosatetraenoic acids (DHETEs), reduces HLI by increasing EETs [47-49]. Upregulation of
CYP2J2 enzyme expression is another way that EET formation can be increased, triggering the inhibition
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of Bach-1 and, thereby, stimulating HO-1 expression. As in the case of sEH inhibition, this CYP2J2
enzyme-stimulated increase in EETs protects against oxidative stress in the lungs and can reduce HLI
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[50]. Possible treatment options for HLI may be found in stimulating CYP2J2 enzyme expression and
warrants further research.

2.3 CYP4A
CYP4A enzymes are a subfamily of extra-hepatic enzymes and are known to hydrolyze arachidonic acid
(AA) into ω-terminal hydroxyeicosatetraenoic acid (20-HETEs) [51]. One important study determined
that inhibition of 20-HETEs resulted in vasoconstriction of the pulmonary arteries (PA), implicated 20-
HETEs as PA tone modulators under hyperoxic conditions, and confirmed the presence of CYP4A
enzymes in human lungs [52]. These results indicate that CYP4A-metabolism of AA into 20-HETEs may
have a beneficial role in maintaining pulmonary vascular tone during hypoxia exposure in the lungs and
may help to mitigate the risk of pulmonary arterial hypertension (PAH) [52-54]. Furthermore, another
study found that the presence of interleukin-1beta (IL-1beta), a pro-inflammatory cytokine associated
with asthma, upregulated CYP4A expression, suggesting that asthma patients may have altered CYP4A
expression resulting in changes to airway reactivity [55]. While it could be postulated that CYP4A
enzymes diminish the harmful effects of hyperoxic lung injury, further research is needed to confirm
their influence and determine possible treatment options from manipulating this reaction pathway. The
contribution pulmonary vascular tone in many pulmonary diseases and conditions, not just hyperoxic
lung injury, signifies the importance of understanding CYP4A enzymatic activity under a multitude of

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circumstances.

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2.4 CYP4F
CYP4F is another subfamily that hydrolyzes endogenous AA into 20-HETEs, but it also contributes to
xenobiotic as well as vitamin E and K1 metabolism [56, 57]. This subfamily has significant physiological

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effects in the liver, kidneys, heart, and brain [57-60]. Similar to CYP1A2 enzymes, CYP4F enzymes may
affect hyperoxic lung injury due to the metabolic products circulating from other organs in the body. As

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in the case of CYP4A enzymes, production of 20-HETEs by CYP4F enzymes can affect vascular tone in
different areas of the body [61, 62]. While 20-HETEs seem to serve as a vasodilator in the lungs, they
have the opposite effect in the heart and kidneys and cause vasoconstriction and contribute to

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hypertension in these organs [63]. An interesting area of research to examine is if 20-HETE production
from CYP4F enzymes in other areas of the body affects the pulmonary vascular tone. The
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interconnectedness of the human body brings into question how enzymes located in other organs may
affect pulmonary diseases. Further research into the pathways and mechanisms of CYP4F enzymes is
needed to understand the role they might play in hyperoxic lung injury.
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3. Role of CYP enzymes in the contribution to hyperoxic lung injury

While some enzymes protect against oxidative stress in the lungs, others can contribute to it. Some of
these enzymes enhance oxidative stress through their production of ROS, while other types alter DNA
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repair pathways, resulting in increased DNA adducts. The enzymes that increase HLI through oxidative
stressed are discussed in depth in the following sections. Figure 3 demonstrates the pathways leading to
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HLI described in these sections.

3.1 CYP1B1
CYP1B1 enzymes and CYP1A enzymes are in the same family and share many characteristics, such as
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portions of homology, AHR transcriptional regulation, and PAH and lipid metabolism [64-66]. Like
CYP1A1 enzymes, CYP1B1 enzymes are found throughout the body, notably in the lungs [67]. The
difference between these two subfamilies stems from the difference in ROS production and contribution
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to oxidative stress. Studies focusing on other physiological pathways have found that CYP1B1 enzymes
reduce ROS and, thereby, protect against diseases induced by oxidative stress [68, 69]. However, similar
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to CYP1A enzymes, CYP1B1 enzymes have been found to have an opposite effect than expected in the
case of hyperoxic lung injury.

Veith et. al. [70] observed that Cyp1b1-/- mice showed decreased lung injury when exposed to hyperoxic
conditions. Because of decreased levels of lipid peroxidation and oxidative DNA adduct recorded in
Cyp1b1-/- mice exposed to hyperoxia, the reduction in pulmonary injury was hypothesized to be caused
by reduced oxidative stress [70]. It was also shown that under normal room air conditions, Cyp1b1-/-
mice showed increased levels of oxidative DNA adduct [70]. These contrasting results may give insight
into one possible mechanism behind how CYP1B1 enzymes contribute to oxidative stress when under
hyperoxic conditions. During hyperoxia exposure, CYP1B1 enzymes may alter DNA repair pathways
rather than increasing ROS generation. The resulting increase in DNA adducts increases pulmonary
injury. More research is needed to further understand the mechanism in which the CYP1B1 enzyme
contributes to hyperoxic lung injury.

3.2 CYP2A
CYP2A enzymes are known for their metabolism of endogenous molecules, such as testosterone, and

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exogenous substances, such as nicotine [71, 72]. The CYP2A family is located in many areas of the
respiratory tract, including the nasal mucosa, trachea, and lungs [73]. As seen in other CYP-mediated

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xenobiotic metabolism, the deactivation of nicotine is oxidative, producing ROS and contributing to
oxidative stress [72, 74]. Several studies have been conducted showing how CYP2A13 enzyme activation
of the nicotine derivative 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) leads to the formation

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of DNA adducts and, eventually, lung cancer [75, 76]. However, more research into the mechanisms
mediating other forms of pulmonary injury by nicotine-metabolism by CYP2A enzymes is needed.

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3.3 CYP2E1
As seen with CYP1A2 enzymes, hepatic CYP2E1 enzymes can have an impact on the physiological

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pathways in the lungs. CYP2E1 enzymes play a crucial role in xenobiotic, especially alcohol and
acetaminophen, metabolism in the liver [77, 78]. Reaction uncoupling during endo- and xenobiotic
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metabolism contributes to ROS levels in the liver and can lead to hepatic diseases, such as alcoholic liver
disease, liver cancer, and non-alcoholic fatty liver disease (NAFLD) [79-82]. Chronic alcohol abuse and
the resulting increased ROS production by ethanol-metabolizing CYP2E1 enzymes contribute to extra-
hepatic disease pathology as well.
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While CYP2E1 enzymes are mainly found in the liver, the release of oxidative stress from these enzymes
can contribute to injury in the lungs [83-85]. Because CYP2E1 enzymes significantly contribute to
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systemic ROS production via enzymatic reaction uncoupling, ethanol metabolism can disturb the redox
balance, contribute to protein, DNA, and lipid oxidation, and result in cellular damage. Therefore,
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ethanol-induced CYP2E1 activity enhances oxidative stress in the lungs, leading to increased pulmonary
inflammation and risk of injury [86, 87]. Studies have also linked increased CYP2E1-mediated ROS
production to increased endoplasmic reticulum (ER) stress and adverse impact on systemic immunity
leading to increased risk of pulmonary infection culminating in ARDS or chronic obstructive pulmonary
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disease (COPD) [88-90]. Mishin et. al. [91] demonstrated that increasing the CYP2E1/CPR ratio did not
alter H2O2 generation [91]. These results call into question if CYP2E1 contributes to ROS production and
warrant further study.
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3. Conclusion
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Because of the diversity and versatility of CYP enzymes, their role in hyperoxic lung injury is significant
but complex. Overall, CYP enzymes share a commonality in their contribution to xenobiotic and
endogenous molecular metabolism; however, the specific molecules they metabolize, their location in
the body, and their mechanisms can differ from one another. CYP1A1/A2, CYP1B1, CYP2E1, CYP2J2,
CYP4A, CYP4F, and CYP2A all seem to have a possible effect on hyperoxic lung injury. The location of
CYP1A1 in the lung and its ROS-producing metabolism of PAHs and HAAs are the most significant signs
that this enzyme impacts hyperoxic lung injury. The surprising result is that CYP1A1 protects against
hyperoxic lung injury by metabolizing lipid peroxide products. Although CYP1A2 is found almost
exclusively in the liver, it serves a similar role as CYP1A1 enzymes in pulmonary injury but does so via
circulation of metabolic products [92]. CYP1B1 shows significant expression in the liver and, to a much
lesser extent, in the lungs [92]. Although in the same family, CYP1B1 enzymes have the opposite effect
than CYP1A enzymes by contributing to hyperoxic lung injury due to the possible alteration of DNA
pathways during hypoxia exposure. In studies comparing CYP enzyme expression in various organs,
CYP2E1 has shown some of the highest expression in the liver and the kidneys [92]. Chronic ethanol
metabolism by CYP2E1 enzymes increases oxidative stress in the lungs and may make patients more
susceptible to inflammation and hyperoxic lung injury.

The presence of CYP2A enzymes in the lungs and their metabolism of nicotine have been shown to

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contribute to oxidative stress. A study examining the effects of CYP2A metabolism of nicotine under
hyperoxic conditions will help understand the connection between these enzymes and hyperoxic lung

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disease. CYP2J2 enzymes, on the other hand, protect against oxidative stress and HLI by increasing EET
expression, which stimulates antioxidant enzymes and modulates pulmonary vascular tone.

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CYP4A and 4F enzymes have less understood research implications on hyperoxic lung injury. CYP4A
production of 20-HETEs has been shown to have vasodilating effects on pulmonary arteries and,

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therefore, may have beneficial effects on pulmonary injury but needs further research to confirm. CYP4F
enzymes produce 20-HETEs just as CYP4A enzymes but are located in the liver. Focused research in 20-
HETE production from CYP4F enzymatic-metabolism and how it impacts hyperoxic lung injury via the

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circulatory system is needed. As exemplified through these enzymes, hyperoxic lung disease is affected
by many different pathways. Research into the mechanisms in which CYP enzymes contribute to or
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protect against hyperoxic lung injury may allow for development of better treatment strategies and
options.

4. Expert opinion
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The research in hyperoxic lung injury have tremendous implications, especially in this current time
period. As the COVID-19 pandemic has shown, mechanical ventilation with oxygen supplementation has
adverse effects on patients. While these patients need the increased oxygen concentration to survive,
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the resulting oxidative stress leads to pulmonary inflammation, infection, and complications.
Understanding the mechanism behind this effect is critical to improving oxygen supplementation
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treatment. CYP enzymes play a critical role in this mechanism that needs to be understood. The ultimate
goal of this field of research would be to understand the stimulating factors causing HLI, formulating a
treatment to counter those stimulating factors, and incorporating this treatment when patients require
supplemental oxygen. Patients who would benefit from this treatment would be COVID-19 patients
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placed on ventilation, adults with acute respiratory distress syndrome, premature infants with
bronchopulmonary dysplasia, patients with chronic obstructive pulmonary disease, and many more.
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Because of the diversity in patients whom this research can benefit, the connection between CYP450
enzymes and hyperoxic lung injury is an exciting field to research. However, the current understanding
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of this relationship is not complete. The challenge with this subject is the complexity of the enzymatic
mechanisms and pathways. Studies are needed to detangle the interconnected nature of the
biomolecular pathways in order to understand the impact of CYP enzymes on pulmonary injury during
hyperoxic conditions. These studies must be enzyme-, organ-, and condition-specific to minimize the
contrasting characteristics of CYP450 enzymes.

CYP450 enzymes are only one biomolecular component that may be utilized to prevent HLI. Other areas
of research may focus on stimulating antioxidant enzymes or eliminating reactive oxygen species
directly. Furthermore, polymorphic SNPs of enzymes are being analyzed to understand the genetic
component that may increase a patient’s susceptibility to disease. Again, the diversity of this field of
research is a major challenge for researchers. Each component plays a role in the process and offers the
opportunity to be manipulated, controlled, or altered for treatment. The challenge lies in the resources,
time, and experimental protocol required to sift through the confounding variables and develop not only
an understanding of the contributing and protective variables but also a treatment that can be
implemented clinically.

Currently, the research in this field is in the “understanding” phase. For example, a flavonoid-rich diet is
theorized to have an antioxidant effect and prevent certain types of cancer; however, this research is

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still preliminary and its true effects are yet to be understood [93, 94]. Each experiment conducted brings
with it a wealth of information, but more of these experiments are needed. The next 5 to 10 years will

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be crucial in taking the research to the next phase of treatment development and implementation.
People around the globe have seen the importance of this research and the need of these patients.
COVID-19 will revolutionize this field, hopefully bringing new studies, knowledge, and treatments with it.

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My hope is that my lab as well as many others can answer the call for help from the public.

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Funding
This paper received funding from the Cancer Prevention and Research Institute of Texas (RP190279), the
National Heart, Lung and Blood Institute (R01HL129794) and the National Institute of Environmental
Health Sciences (1P42 ES0327725, 1R01ES029382).
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
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grants or patents received or pending, or royalties.

Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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Figure legends

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Figure 1: General Overview of the Relationship Between CYP Enzymes and Oxidative Stress. CYP P450
enzymes are oxidizing enzymes that often contribute to the release of reactive oxygen species (ROS),
which in turn contribute to oxidative stress. These enzymes are stimulated by outside factors, such as
pollutants, alcohol, nicotine, endogenous molecules, etc. Antioxidant enzymes help reverse the
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oxidative stress produced by CYP enzymes by lowering ROS accumulation. ROS also serve as a negative
feedback loop to lower CYP enzyme production. Subfamilies of CYP enzymes metabolize many different
types of endogenous and exogenous molecules and can be upregulated and downregulated by a variety
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of molecules. This diagram provides a generalized overview of the relationship between CYP enzymes
and oxidative stress. This relationship can be altered or even reversed under hyperoxic conditions for
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certain types of CYP enzymes.

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Figure 2: Possible Mechanism for Protection of CYP Enzymes from Hyperoxic Lung Injury. Under
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hyperoxic conditions, some CYP enzymes help to protect against hyperoxic lung injury (HLI). CYP2J2
enzymes produce epoxyeicosatrienoic acids (EETs) from arachidonic acid (aa). An increase in EETs
production down regulates Bach-1, an inhibitor of the antioxidant enzyme HO-1. This down regulation of
the inhibitor results in an increase of HO-1 enzymes, resulting in decreased pulmonary oxidative stress
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and HLI. CYP4A and CYP4F enzymes both produce 20-HETEs from their enzymatic cycles. The production
of 20-HETEs have beneficial effects of increasing vasodilation of pulmonary arteries, which also help to
reduce HLI. Hyperoxic conditions alter the effects of CYP1A enzymes on oxidative stress. The
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upregulation of CYP1A enzymes during hypoxia results in reduction of oxidative stress-contributing F2-
isoprostanes/isofurans and DNA adducts. This reduction reduces the production of pro-inflammatory
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cytokines and leads to an overall reduction in HLI.

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Figure 3: Possible Mechanism for Contribution of CYP Enzymes to Hyperoxic Lung Injury. Other CYP
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enzymes have been shown to contribute to hyperoxic lung injury (HLI) by increasing DNA adducts, which
in turn increases pulmonary oxidative stress. CYP1B enzymes are stimulated by polycyclic aromatic
hydrocarbons (PAHs) and alter DNA pathways when exposed to hyperoxic conditions. The alteration of
DNA pathways results in production of DNA adducts, stimulating HLI. CYP2A enzymes are upregulated by
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the presence of nicotine and produce reactive oxygen species (ROS). The ROS production also leads to
an increase in DNA adducts and oxidative stress. CYP2E1 enzymes work similarly to CYP2A enzymes but
break down ethanol rather than nicotine. Both of these enzymes can contribute to HLI when these
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xenobiotics are present.

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