Cytochromes P-450 are responsible for the biotransformation of drugs and other hydrophobic molecules by the liver. Several isoforms coexist which display an asynchronous onset during the perinatal period suggesting the involvement of multiple mechanisms of regulation. In this paper, we have shown that the CYP2E1 protein and its associated activity could not be detected in the fetal liver and rise during the first few hours following birth independently of the gestational age (between 25 -40 weeks). During this period, the CYP2E1 RNA content remains fairly low: the stabilization of the low amount of existing CYP2E1 protein by endogenous ketone bodies could explain the early neonatal rise of the protein level. From 1 month to 1 year, the protein content gradually increases and is accompanied by the accumulation of CYP2E1 RNA, suggesting a transcriptional activation of the gene during the late neonatal period.We examined the methylation status of CpG residues in the 5' flanking region, first exon and first intron of CYP2El gene cleaved with HpIIIMspI. Genomic DNA from fetal liver shows several hypermethylated spots in the first-exon -first-intron region, which progressively disappear in neonatal samples. We conclude that during the neonatal period, the accumulation of hepatic CYP2E1 RNA is correlated with the degree of methylation at the 5' end of the CYP2EI gene.Keywords: human liver; CYP2EI ; hypermethylation ; neonatal period; regulation.The cytochrome P-450 (P-450) gene superfamily (CUP) encodes a group of hemoproteins that mostly catalyze the oxidative metabolism (or monooxygenation) of hydrophobic endogenous compounds like steroids, fatty acids, prostaglandins and exogenous chemicals including drugs, carcinogens and environmental pollutants [I]. These substrates can be converted either to inert polar metabolites further eliminated in a water-soluble form or to cytotoxic or carcinogenic derivatives [2]. CYP2El is a member of this superfamily mainly expressed in the human liver and to a minor extent in the lung [3]; traces of CYP2E1 have also been detected in the small intestine [4] and in the brain [S]. CYP2E1 catalyzes the metabolic activation of chemicals presenting a wide structural diversity, including aromatic compounds, benzene, N-nitrosodimethylamine, halogenated alkanes and others low-molecular-mass compounds which have toxicological implications in humans [6-81. It has also been implicated in the metabolism of drugs and halogenated anesthetics, like acetaminophen, isoniazid, halothane and enflurane 19, 101.Additionally, CYP2E1 is involved in the metabolism of alcohols, aldehydes, ketones and plays a key role in gluconeogenesis from endogenous ketone bodies released in situations involving hormonal or metabolic changes associated with energy deprivation [ 1 1 -131.A general feature of the monooxygenase system is its ability to be activated by exogenous compounds. In this respect, the Enzymes. Cytochrome P-450 (EC 1.14.14.1); glucose-6-phosphate dehydrogenase (EC 1.1.1.49). CYP2E1 content is increased b...

Absrracr: Methylation of dinucleotide CG residues located in the 5' end of the CYP2El gene has been demonstrated to play a role in the control of gene expression in the human developing liver. This study was undertaken to examine the CYP2EI RNA content of human lung, kidney and full-term placenta and to determine whether the expression of CYP2El was controlled by its methylation status in these tissues. CYP2E1 was expressed at a very low level in the lung and kidney at whatever age, and at a variable level in full-term placentas. The restriction profile of genomic DNA was identical in lung and kidney and corresponded to a heavy methylation of HpaIIlMspI sites located within the promoter, the first exon and first intron of the CYP2EI gene. A different pattern of methylation was obtained in full-term placentas, indicating that CpG residues located in the 5' end of the gene were predominantly but not fully demethylated. However, the variable level of CYP2El RNA in full-term placentas suggests the involvement of other elements in the regulation process of CYP2EI in this tissue.CYPZEl is a member of the cytochrome P450 gene superfamily (CYP) (EC 1.14.14.1) that catalyzes the biotransformation of a variety of foreign compounds including ethanol, drugs (halogenated anaesthetics, acetaminophen, muscle relaxants), organic solvents (benzene, styrene, carbon tetrachloride, trichlorethylene) and other low molecularweight compounds (Wrighton et al. 1986;Guengerich & Shimada 1991;. CYP2E1 is capable of activating promutagens like N-nitrosodimethylamine into highly reactive intermediates involved in carcinogenesis (Yo0 et al. 1988). In addition, CYP2El is believed to play a major role in the gluconeogenesis from acetone released during fasting or diabetes (Casazza et al. 1984;Kopp & Casazza 1985).CYP2El is constitutively expressed in the human liver and at a lower level in various extrahepatic tissues including lung, small intestine, placenta and brain (Shimada et al. 1994;Wheeler et al. 1992; Hakkola et al. 1996a & b; Tindberg & Ingelman-Sundberg 1996). The CYP2EI protein content is markedly increased by a set of chemicals showing a wide structural diversity, including its own substrates acetone, isoniazid or pyrazone, but also by fasting and diabetes (Koop et al. 1985; Johansson et ul. 1988;Hong et al. 1987;Dong et al. 1988).In animals, the regulation of CYP2El expression is complex and involves several mechanisms: post-translational by a ligand-dependent enzyme stabilization, translational by stabilization of its RNA in diabetes or transcriptional during ontogenesis (Song et al. 1986(Song et al. & 1989Umeno et al. 1988).In a previous study, we reported ontogeny of CYP2E1 in human liver during the perinatal period: the protein was totally absent from the foetal liver and surged very rapidly within the first hours after birth. This increase was believed to result from a stabilization of the preexisting protein by ketone bodies released at birth without a simultaneous increase of the RNA content. After one month of age, the ...

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