Sequence of the 5'-regulatory region of the patas and cynomolgus monkey CYP2E1 genes: Similarity of the patas to the human polymorphic variant

Nitrosamines are ubiquitous carcinogens activated into DNA-damaging metabolites by cytochrome P450 2E1. PCR-RFLP analysis with RsaI has shown polymorphic variants in the 5'-regulatory region of human 2E1, where a single base change from C to T leads to restriction-site loss. Homozygosity of this allele (c2) associates with increased risk to nasopharyngeal cancer and alcoholic liver disease, and with increased gene transcription. We PCR-amplified this region in monkey DNA using human primers and found a 410 bp product (identical in size to the human product) in 25 patas, but a 800 bp fragment in 6 cynomolgus monkeys. Neither fragment restricted with RsaI. Sequence analysis revealed that all the patas monkeys had an identical RsaI site as a c2c2 human, including the C to T change. Overall homology was 94%. The 100% frequency of c2 in patas is in contrast to humans, where the allele frequency ranges from 2-20%. These results suggest that the c2 CYP2E1 is either primitive or adapted to a particular environment, and that patas are good models for human responses. Nasal cavity epithelium from this species sustained N-nitrosodimethylamine (NDMA)-induced DNA adducts that were 17% of liver values, confirming the putative association of the c2 CYP2E1 with nitrosamine-related cancer risk in this tissue.

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