Developmental Expression of <i>CYP2E1</i> in the Human Liver

Vieira, Isabel; Sonnier, Michelle; Cresteil, Thierry

doi:10.1111/j.1432-1033.1996.0476z.x

Cited by 189 publications

(128 citation statements)

References 50 publications

(26 reference statements)

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“…The first observations of oxidative drug metabolism in human foetal liver were made by Yaffe et al (1970) and Pelkonen et al (1971), and although incomplete, a significant amount of data has been obtained over more recent years about foetal and neonatal hepatic P450 isoforms (Treluyer et al 1991(Treluyer et al & 1996Kitada & Kamataki 1994;Hakkola et al 1994;Vieira et al 1996;Hakkola et al 1998). At birth, total neonatal hepatic cytochrome P450 concentration is approximately 30% of adult levels (Treluyer et al 1996(Treluyer et al & 1997.…”

Section: Cytochrome P450 In the Neonatal Human Livermentioning

confidence: 99%

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Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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Section: Cytochrome P450 In the Neonatal Human Livermentioning

confidence: 99%

“…The ontogeny of CYP2E1 follows a similar pattern to CYP2C and CYP2D6, with very low levels in the human foetus but with rapid postnatal development that may be controlled by the degree of methylation at the 5' end of the CYP2E1 gene (Vieira et al 1996). Nitowsky et al (1966) MiniReview c) CYP3 subfamily.…”

Section: Cytochrome P450 In the Neonatal Human Livermentioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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“…The situation is different in fetal and neonatal liver; a majority of P450 proteins matures postnatally and explains that monooxygenases develop during the early postnatal period (Cresteil et al, 1985;Treluyer et al, 1991;Vieira et al, 1996;Lacroix et al, 1997;Treluyer et al, 1997;Sonnier and Cresteil, 1998). Thus, CYP3A4 is absent from the fetal liver and rises during the first weeks after birth to reach 30 to 40% of the adult level after 1 month of age.…”

Section: Hiv-1mentioning

confidence: 99%

Oxidative Metabolism of Amprenavir in the Human Liver. Effect of the CYP3A Maturation

Tréluyer

Bowers²,

Cazali³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Amprenavir is a human immunodeficiency virus-1 (HIV-1) protease inhibitor intended to be used to treat HIV-infected children. Although a pediatric dosage is proposed by the manufacturer, no data are currently available on the pharmacokinetics of amprenavir in neonates and infants. Amprenavir being primarily eliminated after oxidative biotransformation, we explored its in vitro metabolism by cytochrome P450 (P450)-dependent monooxygenases. In our conditions, five metabolites were formed in vitro and subsequently analyzed by liquid chromatography-mass spectrometry; P450-dependent oxidations occurred either on the tetrahydrofuran ring (M3 and M4), the aniline ring (M5), and the aliphatic chain (M2) or resulted from the N-dealkylation and loss of the tetrahydrofuran ring (M1). The two major metabolites, respectively M3 and M2 were formed by human liver microsomes with K m between 10 and 70 M. CYP3A4 and to a lesser extent CYP3A5 were major contributors for the formation of M2, M3, and M5 metabolites, whereas CYP3A7 had no or little activity. This assumption was confirmed by inhibition with ketoconazole and ritonavir (two potent inhibitors of CYP3A) whereas sulfaphenazole (2C9 inhibitor) and quinidine (2D6 inhibitor) were inefficient. The metabolism of amprenavir was negligible in microsomes from either fetuses or neonates and steadily increased after the first weeks of life in relation with the maturation of CYP3A4/5. In conclusion, results demonstrated that the capacity of the human liver to oxidize amprenavir is low during the first weeks after birth and that dosage could be substantially reduced during the early neonatal period.

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“…Studies using the cytosine methylationdependent restriction endonucleases, HhaI and HpaII, associated the rapid postnatal increase in mRNA expression with DNA demethylation at the 59-region of the gene (Umeno et al, 1988). In the mid-1990s, similar studies of CYP2E1 ontogeny in humans implicated progressive demethylation of specific CpG residues in exon1 and intron 1 with postnatal increases in CYP2E1 mRNA expression throughout the neonatal period (Vieira et al, 1996). Low levels of CYP2E1 mRNA in human fetal, neonatal, and adult kidney and lung tissue were also associated with extensive methylation of the same region of the gene (Vieira et al, 1998).…”

Section: Epigenetic Regulation Of Adme Genes During Developmentmentioning

confidence: 86%