Metabolism of nitrosamines and aflatoxin B1 by hamster liver CYP2A enzymes.
Using a specific antibody against mouse CYP2A5 and coumarin as inhibitors, and pretreatments known to affect the activities of CYP2A-related enzymes, we studied the contribution of hamster liver CYP2As in the dealkylation of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and hydroxylation of aflatoxin B1 (AFB1). CYP2A5 antibody inhibited AFB1 and NDEA metabolism by 40-60% in untreated hamsters and after treatment with phenobarbital (PB) or 3-methylcholanthrene (MC). After pyrazole (PYR) treatment, there was no inhibition, although PYR increased the metabolism above the controls. NDMA metabolism was inhibited only weakly in all groups. This suggests that CYP2As may contribute significantly to NDEA and AFB1 metabolism and less to NDMA metabolism in untreated hamster liver and after MC or PB treatments, but that PYR treatment may change the expression pattern of CYPs so that the metabolism 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 not only with CYP2As but also with other CYPs that are important in nitrosamine metabolism. On the other hand, coumarin inhibited AFB1 metabolism significantly only in control and PB-treated animals but not at all after PYR or MC treatment. This suggests that enzymes involved in AFB1 metabolism may be different depending on the pretreatment. It is concluded that CYP2As may contribute significantly to nitrosamine and aflatoxin metabolism in hamster liver. However, in view of previous results showing essential differences in their regulation between mouse and hamster, interspecies comparisons may be difficult.
Pelkonen
P
P
University of Kuopio, Department of Pharmacology and Toxicology, Finland.
Kirby
G M
GM
Wild
C P
CP
Bartsch
H
H
Lang
M A
MA
D016604:Aflatoxin B1 / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003374:Coumarins / Q000494:pharmacology; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007700:Kinetics; D008297:Male; D008647:Mesocricetus; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009602:Nitrosamines / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000302:isolation & purification / Q000378:metabolism*
D003374:Coumarins; D009602:Nitrosamines; D011720:Pyrazoles; C031280:pyrazole; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; C030123:coumarin; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D010634:Phenobarbital