GENE STRUCTURE AND REGULATION OF N-NITROSODIMETHYLAMINE DEMETHYLASE

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The principal enzyme involved in the metabolism and activation of small nitrosamine compounds is the ethanol-inducible P450IIEI. This enzyme is induced by ethanol, fasting and diabetes through a post-transcriptional mechanism. The IIEI gene becomes transcriptionally activated soon after birth. To study the regulation of the IIEI gene, rat and human genomic clones were isolated and completely sequenced. Both genes contained nine exons similar to other genes in the P450II gene family. Significant nucleotide similarity between both genes was detected within 150 bp of the genes'capsite. The promoter regions were able to drive transcription of the luciferase gene when transfected into rat hepatoma cells. The IIEI was localized to mouse chromosome 7 and human chromosome 10 by use of the somatic cell hybrids mapping strategy. Analysis of the cytosine methylation status of the IIEI gene revealed that sites upstream of the rat IIEI transcription start site are demethylated coincident with transcriptional activation within 24 hours after birth. Methylation changes in the IIEI gene were also detected in humans during development. A Tag I restriction fragment length polymorphism was detected in the human IIEI gene by use of the IIEI cDNA probe.