Expression of CYP2E1 in Human Lung and Kidney during Development and in Full‐Term Placenta: A Differential Methylation of the Gene is Involved in the Regulation Process

Abstract

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 ...

Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment

“…CYP2E1 is expressed postnatally possibly due in part to changes in DNA methylation at the 5Ј-upstream region of the CYP2E1 gene (Vieira et al 1998). Other epigenetic mechanisms may also be involved as suggested by the variable levels of CYP2E1 mRNA in full-term placentas (Jones et al 1992).…”

Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s

“…CYP2E1 Methylation of the CYP2E1 gene inhibits the expression of this enzyme in prenatal period [27]. In adult tissues, the methylation pattern of the CYP2E1 gene differs among various tissue types such as lung, kidney, placenta, liver, and skin, indicating that DNA methylation results in tissue-specific regulation [28,29].…”

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

“…Somewhat similarly, both the rabbit and human FMO1 upstream regulatory domains are highly conserved, despite the fact that rabbit FMO1 is the major isoform expressed in the mature rabbit liver, whereas human FMO1 is suppressed in the immediate perinatal period (Luo and Hines, 2001). Differential methylation has been shown to be involved in the rapid perinatal increase in human CYP2E1 expression (Vieira et al, 1998) and may also play a role in both the onset of DME postnatal expression, as well as the temporal changes in isoform expression. Certainly, much of this evidence remains correlative and, for the most part, speculative.…”