METABOLISM OF NITROSAMINES AND AFLATOXIN B-1 BY HAMSTER LIVER CYP2A ENZYMES

Using a specific antibody against mouse CYP2A5 and coumarin as inhibit ors, and pretreatments known to affect the activities of CYP2A-related enzymes, we studied the contribution of hamster liver CYP2As in the d ealkylation of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (N DEA) and hydroxylation of aflatoxin B-1 (AFB(1)). CYP2A5 antibody inhi bited AFB(1) and NDEA metabolism by 40-60% in untreated hamsters and a fter treatment with phenobarbital (PB) or 3-methylcholanthrene (MC). A fter pyrazole (PYR) treatment, there was no inhibition, although PYR i ncreased the metabolism above the controls. NDMA metabolism was inhibi ted only weakly in all groups. This suggests that CYP2As may contribut e significantly to NDEA and AFB(1) metabolism and less to MDMA metabol ism in untreated hamster liver and after MC or PB treatments, but that PYR treatment may change the expression pattern of CYPs so that the m etabolism is mainly catalysed by CYPs not recognized by the antibody. Coumarin inhibited NDEA and NDMA metabolism in all groups of hamsters, including pyrazole-pretreated animals, suggesting that it interacts n ot only with CYP2As but also with other CYPs that are important in nit rosamine metabolism. On the other hand, coumarin inhibited AFB(1) meta bolism significantly only in control and PB-treated animal but not at all after PYR or MC treatment. This suggests that enzymes involved in AFB(1) metabolism may be different depending on the pretreatment. It i s concluded that CYP2As may contribute significantly to nitrosamine an d aflatoxin metabolism in hamster liver. However, in view of previous results showing essential differences in their regulation between mous e and hamster, interspecies comparisons may be difficult.