Developmental expression of CYP2E1 in the human liver - Hypermethylation control of gene expression during the neonatal period

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 tron and first intron of CYP2E1 gene cleaved with HpaII/MspI. 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 CYP2E1 gene.