JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 8, Number 3, 1998

Mary Ann Liebert, Inc.
Pp. 161-174

A Review of Developmental Aspects of Cytochrome P450

JESSICA R. OESTERHELD, M.D.

ABSTRACT

This article surveys the development of human hepatic P450 cytochromes (CYPs) involved
in xenobiotic metabolism from the fetus through the life span and explores possible clinical
consequences of developmental issues. These hepatic P450 CYPs come "on line" at different
times during fetal and infant development, and each one is discussed in that temporal se-
quence. CYP3A7. the major fetal hepatic cytochrome, is present during organogénesis, and
it is involved in steroid metabolism. Variably expressed in some fetuses, CYP3A5 is also pres-
ent at significant levels in about half of all children. In adults, CYP3A4 is the major func-
tional member of the CYP3A subfamily. CYP1A1 is also present during organogénesis, and
it metabolizes exogenous toxins, some of which are procarcinogens. CYP2E1 may be pres-
ent in some second-trimester fetuses, and it may be involved in prenatal alcohol metabolism.
After birth, hepatic CYP2D6 and CYP2C8/9 and CYP2C18/19 become active. Both CYP2D6
and CYP2C19 have genetic polymorphisms that can bring about differing capacities to me-
tabolize exogenous drugs, including psychotropic drugs. CYP1A2 becomes active in the
fourth to fifth postfetal months. It provides the best current examples of the importance of
developmental changes in xenobiotic-metabolizing P450 CYPs through its metabolism of caf-
feine and theophylline in premature infants, neonates, and adolescents.

Locatedkidney—P450 cytochromes (CYPs)

and
primarily in liver and small intestine—as well as in other organs, including the lungs, brain,
are enzymes that metabolize both endogenous and exogenous
substrates. There are two classes of P450 CYPs: endogenous CYPs found in mitochondria (which in adults
metabolize the body's own prostaglandin, steroids, and cell wall proteins) and exogenous CYPs, found in
smooth endoplasmic reticulum (which metabolize xenobiotics: toxins, mutagens, carcinogens, and drugs,
including psychotropic drugs).
The amino acid sequences of P450 CYPs have been determined, and a classification system based on
grouping CYPs by similarity of amino acid structure has been developed. P450 CYPs are named by stat-
ing the broadest group first and then naming increasingly similar groups, e.g., family (1 to 4), subfamily

Division of Child and Adolescent Psychiatry, University of South Dakota School of Medicine, Sioux Falls, South
Dakota.
Although I wish to thank Dr. David A. Flockhart for his helpful criticism of this paper, I claim any errors as solely
mine.

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 OESTERHELD

(A-E), and isoform (1,2, etc; a CYP

designation refers to the enzyme as well as the gene that encodes the
enzyme). Important xenobiotic-metabolizing P450 CYPs include CYP1A1/2, CYP2C8/9, CYP2C18/19,
CYP2D6, CYP2E1, and CYP3A4/5/7 (closely related isoforms within a family of CYPs are grouped to-
gether). Each of these P450 CYPs has a particular set of inhibitors and inducers that decreases or increases
enzyme activity, and each CYP metabolizes particular substrates.
Yaffe and associates (1970) first identified xenobiotic-metabolizing P450 CYPs in fetal hepatic cells in
1970. In recent years, there has been an explosion of information about these P450 CYPs from data gen-
erated through new research techniques (specific antibodies, metabolic probes and inhibitors, and recom-
binant cDNA enzymes) that are sensitive to very low levels of enzymes and express individual isoforms in
quantity (polymerase chain reaction). There have been several preliminary reviews of fetal hepatic P450
CYPs or of developmental aspects of hepatic xenobiotic P450 CYPs (Hakkola et al. 1988; Hulla and Juchau
1989; Juchau et al. 1980; Juchau et al. 1992; Kearns 1995; Krauer and Dayer 1991; Raucy and Carpenter
1993; Rich and Boobis 1997; Rogers 1994; Wrighton and Stevens 1992).
I will first discuss fetal hepatic P450 CYP studies: mRNA studies that may predict functional CYPs and
studies that have isolated and purified P450 CYPs. I will then take up the xenobiotic-metabolizing hepatic
P450 CYPs in the same sequence as they come "on line," from the first trimester of the fetus through in-
fancy (Table 1).
I will also describe what is known about the maturation of each hepatic xenobiotic-metabolizing P450
CYP through the life span and speculate about possible clinical consequences. As asynchronous as these
CYPs are in coming on line, so too are they in going "off line." Although the total hepatic CYP metabo-
lism declines in the aged (Sotaniemi et al. 1997), only particular CYPs decrease. Finally, CYP1A2 and its
relationship to the metabolism of caffeine and theophylline and to puberty will be discussed as the best cur-
rent examples of the clinical importance of development of hepatic xenobiotic P450 CYPs.

FETAL HEPATIC mRNA STUDIES

Techniques that identify mRNA can establish the possibility of later functional fetal CYPs. Two sub-
families of CYP mRNA have been found in the first trimester of fetal development during organ develop-
ment (from 18 to 60 days). Researchers have identified CYP3A7 mRNA and CYP3A5 mRNA after only
42 days of development (Schuetz et al. 1994). Hepatic CYP1A1 mRNA has been detected as early as fe-
tal day 45 (Omiecinski et al. 1990; Yang et al. 1995).
In the second and third trimester, mRNAs of CYP2C8/9, CYP2C18, CYP2D6, CYP3A4/5, and CYP3A7
have been found (Greuet et al. 1996; Hakkola et al. 1994; Treluyer et al. 1997). One study showed that
CYP2E1 mRNA is present at 16 to 18 weeks when it was not present at 10 weeks of fetal life (Carpenter
et al. 1996). Another study failed to support this finding in livers of fetuses after 10 to 17 weeks of devel-
opment (Jones et al. 1992). Three explanations can account for the discrepancies between these studies: a
limited number of fetuses over the age of 16 weeks were evaluated, techniques varied between studies, or

Table 1. When CYPs Come "On Line"

Present in fetus Present in fetus in Appears at 3-4

in first trimester 2nd and 3rd trimester Appears after birth monthsafter birth
CYP3A7 CYP3A7a CYP2D6 CYP1A2
CYP1A1 CYP1A13 CYP3A4
CYP3A5a CYP2C9
(CY02El)b CYP2C18/19
(CYP2D6)b CYP2E1
(CYP2Cs)b
"Purified by Kitada, Kamataki, Komori, and associates.
bVariably expressed.
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 DEVELOPMENTAL ASPECTS OF CYTOCHROME P450

MOTHER PLACENTA FETUS

Pregnenolone

LIVER
"1
Progesterone

Estradiol
+
Estrone

t
DHEA-S .J
I
DHEA-S —I
CYP3A7I

_I
LIVER

"site of action of CYP3A7 in fetal liver and placenta

adapted from Rane et al. 1992

FIG. 1. Maternal-placental-fetal metabolism of steroids. CYP3A7 site of action.

CYP2E1 mRNA may be present in only a proportion of second-trimester fetuses (Carpenter's study
small
showed that CYP2E1 mRNA is variably expressed in second-trimester fetuses).

PURIFIED FETAL HEPATIC P450 CYPs

In a series of studies, Kitada, Kamataki, Komori and associates have identified and purified four hepatic
P450 CYPs in fetuses after approximately 20 weeks of development (1) CYP3A7 (P-450HFLa); (2) CYP3A5
(P-450HFLC); (3) a member of the CYP1A family (P-450HFLb); and (4) a CYP that has yet to be charac-
terized (Kitada et al. 1985; Kitada et al. 1987b; Kitada et al. 1991; Kitada et al. 1992; Kitada and Kamataki
1994; Komori et al. 1989; Komori et al. 1990; Ohmori et al. 1994).

CYP3A7: THE MAJOR FETAL HEPATIC P450 CYP

Not only is CYP3A7 present by 50 to 60 days of fetal life, but it is also the most abundant hepatic P450
CYP in the fetus (Yang et al. 1994). In fetuses 20 weeks of age, it accounts for one third of the total fetal
CYP content (Kitada et al. 1985). Purified to homogeneity (Kitada et al. 1991; Komori et al. 1989; Wrighton
and Vandenbranden 1989), CYP3A7 has been found to have a slightly higher molecular weight than other
members of the CYP3A subfamily (Wrighton and Vandenbranden 1989). CYP3A7 and CYP3A4 share 95%
nucleotide identity and 87% amino acid identity (Hashimoto et al. 1993). CYP3A7 is also found in fetal
kidneys, lungs, adrenals and thymus (Kitada and Kamataki 1994). In in vitro systems, CYP3A7 metabolizes
substrates such as testosterone, erythromycin, TAO, nifedipine, aldrin, quinidine, benzo(a)pyrene, 7-ethoxy-

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 OESTERHELD

coumarin, ethylmorphine, N,N-dimethylaniline, aminopyrine, p-nitroanisole, cortisol, N-methylaniline, N,N-

dimethylnitrosamine, indinavir and midazolam (Chiba et al. 1997; Hulla and Juchau 1989; Kitada et al.
1985; Kitada and Kamataki 1994; Ladona et al. 1989; Li et al. 1996; Raucey and Carpenter 1993), but it
has been shown to have poor correlation with aniline hydroxylation and benzphetamine /V-demethylation
(Kitada et al. 1987a).
Protection of the fetus from maternal and fetal steroids is a function of fetal CYP3A7. It is postulated
(and has been shown in in vitro systems by Kitada et al. 1987b and Kitada and Kamataki 1994) that CYP3A7
in fetal liver is responsible for part of the 6-beta hydroxylation of testosterone and 16-alpha hydroxylation
of dehydroepiandrosterone 3-sulfate (DHEA-S), a step in the metabolic pathway to estriol (Raucey and Car-
penter 1993) (Fig. 1).
The fetal adrenal modestly participates in metabolism of DHEA-S, and it is predominantly involved in
the metabolism of progesterone (Rane et al. 1992). CYP3A7's ability to metabolize fetal and maternal
steroids helps protect the fetus from toxic effects of maternal steroids and DHEA-S, which is known to be
toxic to the fetus in high concentrations (Schuetz et al. 1993). The interrelationships between steroid me-
tabolism, estrogens, and 16-alpha hydroxylation in the fetus is a complex one (Milewich et al. 1986). Dex-
amethasone is known to induce DHEA-S metabolism in the more developed fetus (Schuetz et al. 1993).
Maternal estrogen is believed to regulate 16-alpha hydroxylation. Support for this hypothesis has been fur-
thered by the discovery of three estrogen and progesterone response elements in an area of the CYP3A7
gene (Itoh et al. 1992). The increased capacities of metabolism for 16-alpha hydroxylation in the fetus is
lost after birth. It was believed that CYP3A7 was unique to the fetus, but it is now known that it is also
present in placental and uterine tissue (Schuetz et al. 1993). In these extra hepatic sites, CYP3A7 may con-
tribute to the alpha and beta hydroxylation of maternal/fetal steroids (Fig. 1).

CYP3A SUBFAMILY THROUGH THE LIFE SPAN

The CYP3A subfamily is variably expressed in the liver at different life stages. High levels of CYP3A7
and small amounts of CYP3A5 exist during fetal life (Wrighton et al. 1990; Yang et al. 1994). CYP3A7
ceases to be the principal hepatic CYP3A at birth, and CYP3A4 comes "on line" soon after birth. The shift
occurs within the first days of life (Lacroix et al. 1997; Nakamura et al. 1998; Vauzelle-Kervroedan et al.

1996). Premature infants have one third of the total hepatic CYP3A activity of full-term infants for up to
14 days after their birth (Nakamura et al. 1998). At birth, full-term infants have approximately twice the
CYP3A activity of adults, but by the 5th day of life, they have less than half of adult activity (Nakamura
et al. 1998). This sequence of CYP3A changes may be the basis for the observation that midazolam dos-
ing requirements for neonates are lower than those required for older infants (Burtin et al. 1994). Because
premature infants have significantly less CYP3A activity than full-term neonates, clinicians should reduce
dosing of medications metabolized by the CYP3A subfamily (e.g., midazolam, erythromycin). CYP3A4
reaches 30% to 40% of adult activity by the first postnatal month (Lacroix et al. 1997). In adults, CYP3A7
is variably expressed in small amounts (Greuet et al. 1996; Kitada et al. 1985).
CYP3A5 is more commonly expressed in children and teens, as compared with adults, but it is not pres-
ent in all children (47%, Wrighton et al. 1990), nor is it gender specific in this age group. CYP3A4 is the
predominant 3A CYP during adulthood. The mRNA of CYP3A5 has been located in 23% of adult livers,
without gender specificity (Schuetz et al. 1994), and it is expressed in 24% of adults (Wrighton et al. 1990).
Hepatic P450 CYP activity declines with age (Sotaniemi et al. 1997), and it is likely that the CYP3A
subfamily activity also declines with age (Sotaniemi et al. 1996). Not all studies have supported the decline
in CYP3A activity (Hunt et al. 1992a; Hunt et al. 1992b). Age-related decline in the clearances of known
CYP3A substrates, such as erthyromycin, verapamil, quinidine, and midazolam, may reflect in part the 5%
decline in CYP3A content in each decade (George et al. 1995). If this finding is confirmed, the clinical dic-
tum of drug dosing reductions for the elderly (because of age-related factors, e.g., reduced glomerular fil-
tration rate, multiple drugs) may be fine tuned to also consider drugs metabolized by age-sensitive P450
CYP3As. Many drugs could be affected: calcium channel blockers, some short-acting benzodiazapines,

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 DEVELOPMENTAL ASPECTS OF CYTOCHROME P450

some neuroleptics including pimozide and quetiapine, some anti-convulsants such as carbamazepine, azole
antifungals, antiretrovirals, many antitumor drugs, and others (Ketter et al. 1995).
Some investigators have not demonstrated differences in CYP3A content between genders (George et al.
1995), but as reviewed by Harris and associates, the majority of researchers have shown women to have
higher CYP3A activities than men (1996). Several probes have been used: erythromycin (Hunt et al. 1992a),
prednisolone and methylpredisolone (Gleiter and Gundert-Remy 1996), and midazolam and verapamil (Har-
ris et al. 1996). If this gender difference is substantiated and is shown to be clinically significant (other gen-
der differences may be more important, e.g., relating to glomerular filtration rate, glucuronidation), clini-
cians will be able to use this information as one component in adjusting dosing of CYP3A substrates in
women.

INTERINDIVIDUAL VARIATIONS IN CYP3A EXPRESSION

Not only can expression of CYP3A isoforms shift over a lifetime, but the amounts of different isoforms
of CYP3A vary between individuals. This leads to large variations in metabolizing capacities between in-
dividuals because CYP3A isoforms metabolize both unique substrates and overlapping substrates at differ-
ing rates. For instance, in adults, CYP3A4 is responsible for the bulk of metabolic processes (e.g., alfen-
tanil, pimozide, sildenafil, lovastatin, erythromycin, cyclosporine, cocaine, quinidine, nifedipine, and
midazolam [Hakkola et al. 1998; Li et al. 1995]). CYP3A5 metabolizes fewer substrates: nifedipine, mi-
dazolam, cyclosporine, testosterone, estradiol, DHEA-S, and cortisol (generally less efficiently than CYP3A4
except for nifedipine [Gorski et al. 1994; Hakkola et al. 1998]). It does not metabolize, or metabolizes
poorly, quinidine, benzo(a)pyrene, erythromycin, 17-alpha ethylestradiol, and aflatoxins (Gorski et al. 1994;
Hakkola et al. 1998; Wrighton et al. 1990). CYP3A subfamily members also show variations in efficiency
'
of different metabolic pathways of the same substrate (e.g., 1 and 4' hydroxylations of midazolam [Gorski
et al. 1994]).
The importance of knowing P450 CYP3A isoform substrates is illustrated in the following clinical ex-
ample. The erythromycin breath test is used as a probe to assess CYP3A activity, and it is used to predict
daily requirement of cyclosporine in patients after organ transplantation. Because underdosing of cy-
closporine can lead to organ rejection, it is critical to adequately maintain blood levels of cyclosporine. Be-
cause CYP3A5 (present in 20% to 30% of adults and about 50% of children) metabolizes cyclosporine but
does not metabolize erythromycin (Gorsky et al. 1994), the erythromycin breath test cannot measure
CYP3A5's contribution to cyclosporine metabolism. Midazolam metabolism would reflect all of the CYP3A
activities and therefore would be a better predictor of cyclosporine metabolism.

CYP1A1: A P450 CYP PRESENT IN THE FETUS

In adults, CYP1A1 is largely extrahepatic, but its mRNA (Murray et al. 1992; Omiecinski et al. 1990)
and isoform (Kitada et al. 1992; Shimada et al. 1996) have been identified in samples of fetal liver after as
little as 45 to 60 days of development (during organogénesis) (Yang et al. 1995). Levels of fetal hepatic
mRNA CYP1A1 tend to increase with increasing fetal age (Omiecinski et al. 1990).
CYP1A1 metabolizes substrates that are procarcinogens (e.g., benzo(a)pyrene), and it is highly inducible
by certain dioxins and aromatic hydrocarbons, many of which are procarcinogens. This mechanism of in-
duction of CYP1A1 is the best understood of all of the CYPs. The aromatic hydrocarbon receptor, a cy-
tosolic heterodimer, is the sensor and regulator of CYP1A1 induction (Gonzalez et al. 1993). This recep-
tor has been found in most tissues, and it has been identified in the fetus (Okey 1990). It interacts with a
regulatory element upstream of the CYP1A1 gene and increases CYP protein through gene transcription.
(More complete descriptions of the aromatic hydrocarbon receptor are provided by Bock 1994; Gonzalez
and Lee 1996; Hakkola et al. 1998).

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 OESTERHELD

CYP2E1: A P450 CYP THAT IS VARIABLY EXPRESSED IN

FETAL LIFE AND APPEARS AFTER BIRTH

CYP2E1 appears at 16 to 24 weeks of fetal development in some but not all second-trimester fetuses of
mothers without history of a alcohol abuse. Fetal CYP2E1 has a slightly lower molecular weight than the
adult form. It has been suggested that fetal and adult CYP2E1 differ in mRNA splicing sites of this highly
methylated CYP2E1 gene (Carpenter et al. 1996). Fetal microsomes can metabolize aniline, A/-nitrosodi-
methylamine (to its carcinogenic metabolite), halothane, and acetaminophen (to its hepatotoxic metabolite),
all known 2E1 substrates (Raucy and Carpenter 1993). In the 19-week-old fetus, CYP2E1 can metabolize
ethanol to acetylaldehyde at 12% to 27% of the adult rate. In vitro, CYP2E1 appears inducible by alcohol
and clofibrate but not by rifampin (Carpenter et al. 1996).
The presence of CYP2E1 in mid-trimester fetal tissue has not been confirmed by Vieira et al. (1996).
Their studies show that CYP2E1 protein becomes active immediately after birth, regardless of gestational
age. They postulate that the fasting neonate's release of acetone acts as the triggering mechanism. A demethy-
lation at the 5' end of the gene presages the accumulation of CYP2E1 mRNA after 1 month of postnatal
age. The levels of CYP2E1 content gradually increase through the 7th week when it reaches 40% of adult
values, and it remains fairly constant through the first year (Vieira et al. 1996). Using A/-demethylation of
A/-nitrosdimethylamine as a probe, one group of investigators found CYP2E1 content unchanged in elderly
subjects (Hunt et al. 1990), but lack of specificity of this probe for only CYP2E1 and small sample size
make this study suspect (George et al. 1995). It is likely that the content of this CYP declines with age (Re-
oger et al. 1995). If this is shown to be true and quantitatively significant, clinicians will need to reduce
dosing for CYP2E1 substrates, e.g., anesthetics including halothane, felbamate, acetaminophen, and others.

ENZYMATIC SYSTEMS THAT CONTRIBUTE TO XENOBIOTIC TERATOGENESIS

This new information about fetal xenobiotic hepatic P450 CYPs has radically altered the view of the fe-
tus from a passive entity protected by a maternal barrier to an active metabolizing entity. The ability of the
fetus to metabolize xenobiotics has its advantages and disadvantages. Although agents such as aflatoxin B1,
ethanol, and steroids can be detoxified by the fetus, these CYPs also can create metabolites that can be toxic
to the developing fetus. Because most metabolites are more water soluble than their parent compounds, they
cannot diffuse across biologic membranes and are trapped on the fetal side. In the fetus, the enzymes of
phase 2 metabolism have not yet matured. This situation persists for premature infants and normal new-
borns because glucuronidation has not yet become active (Capparelli 1994) and acetylation may not de-
velop until the 4th postnatal year (Pariente-Khayat et al. 1997).
Fetal hepatic CYPs have high mutagen-activating abilities (Kamataki et al. 1992). CYP3A7 also can activate
promutagens: aflatoxin Bl, 2-amino-3-methylimidazo(4,5-f)quinoline (IQ), 2-amino-6-methyldipyrido(l,2-al-
pha:3',2'-d)imidazole acetate (Glu-P-1), 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline (MelQ), sterigmato-
cystin and others (Hakkola et al. 1998; Kamataki et al. 1992; Kitada et al. 1989; Kitada et al. 1990; Kitada and
Kamataki 1994; Shimada et al. 1996). There is evidence that two hepatic CYPs are involved in fetal metabo-
lism of benzo(a)pyrene: one constitutive (CYP3A7) and the other induced (CYP1A1) (Raucey and Carpenter
1993). These fetal reactions may be associated with carcinogenesis, mutagenesis, and dysmorphogenesis.
Similarly, in adults, hepatic P450 CYP2E1 has been shown to metabolize many foreign substances that
are known to be hepatotoxic or carcinogenic (Lieber 1997). This new information about hepatic P450 CYPs
is merely the "tip of the iceberg," and further research in this area may provide a more comprehensive un-
derstanding of the toxic effects of xenobiotics in the fetus and throughout the life span.
Because fetal hepatic P450 CYPs have limited metabolic capacities (Hakkola et al. 1998), they may make
crucial but local contributions (Juchau et al. 1992) to xenobiotic teratogeneis. They are only one of the en-
zymatic systems that contribute to xenobiotic teratogenesis: others include prostaglandin H synthase, lipoxy-
genases, and myeloperoxidases (Hakkola et al. 1998; Wells et al. 1997). The placenta also may play a piv-
otal role in teratogenesis both by fetal transfer of xenobiotics and metabolism of some xenobiotics and
endogenous substances by its own limited enzymatic systems, (especially P450 CYP1A1, CYP3A7,
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 DEVELOPMENTAL ASPECTS OF CYTOCHROME P450

CYP19A1, aromatase, involved in the metabolism of androgens to estrogens, Hakkola et al. 1998, McRo-
bie et al. 1996). The placenta is not a barrier to fetal entry; rather, placental-fetal transfer de-
protective
pends on passive diffusion. Factors that can influence placental-fetal transfer include placental blood flow,
pH, and properties of the xenobiotic: lipid solubility, protein binding, molecular weight and so forth (Hakkola
et al. 1998). Crucial data about what controls maternal-fetal circulation within the placenta awaits further
study.

CYP2D6: A P450 CYP THAT IS VARIABLY EXPRESSED IN

FETAL LIFE AND APPEARS AFTER BIRTH

CYP2D6 mRNA gradually increases with the age of the fetal and neonatal samples, and it reaches val-
ues exceeding adult levels soon after birth (Jacqz-Aigrain and Cresteil 1992; Treluyer et al. 1991). Although
most fetal livers have been shown to lack CYP2D6 activity (Ladona et al. 1991; Treluyer et al. 1991), 30%
of mid-trimester fetuses possess it (Jacqz-Aigrain and Cresteil 1992; Treluyer et al. 1991). There is a post-
natal increase in the levels of CYP2D6 protein that is independent of gestational age and appears to be di-
rectly birth related (Jacqz-Aigran and Cresteil 1992; Treluyer et al. 1991). Neonates up to 8 days of age
have about 25% of adult levels of CYP2D6 activity, and this increases with age. Infants 7 to 28 days of
age may exhibit up to 50% of adult CYP2D6 activity, but large interindividual variations exist (Jacqz-
Aigrain and Cresteil 1992; Treluyer et al. 1991). CYP2D6's activity has been shown to be unaffected by
aging (Laurent Kenesi et al. 1996). Its activity is increased during pregnancy (Wadelius et al. 1997) and
should be considered as a factor in dosing of CYP2D6 substrates during this time.
CYP2D6's well-known polymorphism (a stably inherited trait due to a difference in DNA sequence at
1% or higher in a population) is known to be present in children presumably from its earliest expression
(Evans et al. 1989). Almost 8% of white children and 2% of African-American children under 18 years of
age were poor metabolizers (Relling et al. 1991). These data are consistent with known adult rates of this
polymorphism (i.e., 7% to 10% of whites and 1% to 2% of African-Americans). Many drugs, including
psychotropics, are metabolized in part by CYP2D6 (e.g., beta-blockers, codeine, tricyclics, and some neu-
roleptics [Kroemer and Eichelbaum 1995]). This genetic variability in metabolizing capacities is present
throughout childhood and adolescence, and it is unchanged in the elderly (Laurent-Kenesi et al. 1996). It
may be overlooked in explaining individual dosing and side effect differences in individuals taking med-
ications that are known substrates of CYP2D6.

CYP 2 SUBFAMILY: CYP2C8/9 AND CYP2C18/19

In most studies, the CYP2C subfamily of 2C8/9 and 2C18/19 has not been well differentiated. In the fe-
tus and neonate, CYP2Cs are minimally expressed or contained within a few randomly distributed parenchy-
mal cells (Hakkola et al. 1994; Maenpaa et al. 1993; Ratanasavanh et al. 1991; Shimada et al. 1986; Tre-
luyer et al. 1997). In the first 24 hours after birth, the level is virtually undetectable (Treluyer et al. 1997).
After that, the CYP2C subfamily develops in increasing amounts, so that after the first month, one third of
the adult level is attained (Treluyer et al. 1997).
CYP2C8 may be at higher levels after the first postnatal year (Tateishi et al. 1997). After the first week
after birth, CYP2C9 increases to less than half of adult values and declines slightly through the first year
(Treluyer et al. 1997). Use of the n-demethylation of diazepam as a probe of the early development for
CYP2C19 in this study is problematic because CYP3A4 and small amounts of CYP2C9 are also contribu-
tors to this reaction (Jung et al. 1997; Ono et al. 1996; Treluyer et al. 1997).
There is evidence that, in the newborn, CYP2Cs are inducible by barbiturates and steroids (Treluyer et
al. 1997). Because phenytoin, valproate, and diazepam are partially metabolized by CYP2Cs and these
agents are used in the treatment of newborns and infants, clinicians must not inadvertently lower levels of
these medications below the effective range by coadministering CYP2C inducers. There is little evidence
that CYP2C family content declines with age: the half-lives of diazepam, omeprazole, and S-mephenytoin,

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 OESTERHELD

all substrates of CYP2C19, increase with age (George et al. 1995; personal communication D.A. Flockhart,
1998).
Adults share wide interindividual expression in the subfamilies of CYP2C8, CYP2C9, CYP2C18, and
CYP2C19 (Ioannides 1995, pp. 167-168), and it is likely that this is also true in children and adolescents.
Like CYP2D6, a genetic polymorphism of CYP2C19 creates a subgroup of poor metabolizers. As a result,
13% to 23% of Asians and 2% to 3% of whites and Afro-Americans (Marinac et al. 1996) may have higher
than expected levels of substrates of CYP2C19 (e.g., tertiary tricyclics, diazepam, etc. [de Moráis et al.
1995]). Fewer than five whites in 1000 are slow metabolizers of both CYP2D6 and CYP2C19, and they
would be at particular risk for high levels of substrates, which are partially metabolized by both systems
(e.g., some tricyclics and propranolol [Flockhart 1995]). Allelic variations also may exist for CYP2C9, and
about 1% of whites may be poor metabolizers (Sullivan-Klose, 1996). Drugs at least partially metabolized
by CYP2C9 include s-warfarin, nonsteroidal antiinflammatory drugs, phenytoin, fluoxetine, and others
(Oesterheld and Shader 1998). Caution should be exercised in prescribing these medications to this vul-
nerable group. There is insufficient evidence at this time to demonstrate gender differences in CYP2C ac-
tivities (Harris 1996; Xie et al. 1997).

CYP1A2: A CYP THAT APPEARS AT THE 4TH TO 5TH POSTNATAL MONTH

Although the metabolism of caffeine and theophylline is complicated, it provides the best example of
how development of CYPs informs clinical treatment (Fig. 2).
Several CYP isoforms are involved in the metabolism of caffeine and theophylline (Gu et al. 1992).
CYP1A2 is involved in all demethylations and ring hydroxylations. CYP2E1 is involved in n-7 and n-1
demethylations and 8-hydroxylations of caffeine, theophylline, and theobromine as well as the n-3 demethy-
lation of theophylline. CYP2A6 is involved only in n-7 demethylation of theobromine and 8-hydroxylation
of paraxanthine. CYP3A4 is involved in the 8-hydroxylation of caffeine and theophylline, but CYP3A5 cat-
alyzes only the 8-hydroxylation of caffeine. In adults (and presumably in children), there are two distinct
systems that metabolize the 8-hydroxylation of theophylline: a low-capacity/high-affinity system involving
principally CYP1A2 and a high-capacity/low-affinity system involving principally CYP3A4/5 and CYP2E1,
the latter acting as a "catch-all" reservoir (Zhang and Kaminski 1995).
Although CYP1A2 is not present in quantity during fetal life (Ratanasavanh et al. 1991), the fetus can
demethylate caffeine in vitro (Cazeneuve et al. 1994). CYP3A7 may be responsible, and that assertion is
supported by evidence that both levels of CYP3A7 and demethylation capacity decline in late pregnancy
(Cazeneuve et al. 1994; Kitada et al. 1987b). Clinical documentation for CYPlA2's gradual emergence in
the early months of postnatal life is widely available because theophylline and caffeine are extensively used
for the treatment of apnea in premature deliveries, newborns, and infants. In premature infants, caffeine is
metabolized only to theophylline and is excreted in the urine (Berthou et al. 1988). When CYP1A2 devel-
ops after the 3rd to 5th month of life (Sonnier and Crested 1998), n-demethylations begin, and the infant
demonstrates the metabolic pattern that characterizes mature hepatic metabolism (Berthou et al. 1988; Kraus
et al. 1993). The demethylation of imipramine is partially metabolized by CYP1A2, and it exhibits these
same developmental pharmacokinetics (Sonnier and Crested 1998).
Demethylation at n-3 and n-7 increases gradually to a plateau at 4 months of age (Cazeneuve et al. 1994).
Hydroxylation matures as early as 1 month in some children and may be higher in infants than in adults.
N-1 Demethylation is unchanged throughout the first 19 months (Carrier et al. 1988). Why the n-1 demethy-
lation pathway and n-7 demethylation pathway should differ in maturation despite being serviced by the
same CYPs is not known but may relate to different catalytic rates for dissimilar reactions.
Data about theophylline clearance support this maturational CYP process. In newborns, theophylline is
handled via two processes: it is cleared by the kidney as unchanged drug, and it is methylated at the 7 po-
sition to caffeine (Troger and Mayer 1995). Clearance of theophylline reaches adult values 4 to 5 months
postnatally and is primarily related to the maturation of the CYP1A2 pathway (Kraus et al. 1993). Theo-
phylline metabolism is greatest from 3 to 5 years of age and decreases by 50% between 8 and 16 years of
age before reaching adult levels (Troger and Meyer 1995). Using 3-demethylation of caffeine (an indirect

168
 DEVELOPMENTAL ASPECTS OF CYTOCHROME P450

(C-80H)CYP1A2 3
1,3,7THX*
CYP3A4/5, CYP2E1 w
CO

(C-80H) (C-80H)
D CYP2E1
1.3THX CYP1A2
„
N^-CYP1A2
3,7 THX co
co CYP2E1
CYP3A4

7 THX 1 THX 3 THX

xanthine
oxidase

O
II 1 U
CH,
1,3,7 THX* CAFFEINE
=
=
1,3,7 THX* 1,3,7 U 1,3,7-TRIMETHYL URIC ACID
=

(CAFFEINE) 1,7THX PARAXANTHINE

=

3,7THX THEOBROMINE
=

1,3THX THEOPHYLLINE
=

1,3,U 1,3 DIMETHYL URIC ACID

ck
=

3,7 U 3,7 DIMETHYL URIC ACID

=

FIG. 2. Caffeine and theopyhlline metabolism. CYP activity.

measure of CYP1A2 activity) via the caffeine breath test in a group of children, it was confirmed that la-
tency age children had high levels of CO2 and that those high levels decreased in boys in late puberty and
in girls in early puberty (Lambert et al. 1986).
It is well known that prepubertal children can require dosing of psychotropics metabolized by the liver
at higher doses than adults. Adult drug requirements are established around puberty. Regrettably, the sup-
porting evidence is spotty, and there is a dearth of reliable research focused on pubertal changes in hepatic
P450 CYPs. It must remain a hypothesis only, but consistent with known data (e.g., the data from Lambert
et al. 1986 and others), that P450 hepatic CYP changes in metabolic capacity at puberty explain the de-
scribed dosing shifts.

CONCLUSION
In the past few years, there has been an avalanche of new research in developmental aspects of human
hepatic xenobiotic P450 CYPs. This article surveys this area with special emphasis on possible clinical con-
sequences. In the future, researchers will "flesh out" the many unknown areas of xenobiotic-metabolizing
P450 CYP development, and informed clinicians will be able to use this information to better understand
the effects of toxins and drugs in fetal development and to hone their prescribing decisions for patients
throughout the life span.
169
 OESTERHELD

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174