AFLATOXIN-B1 METABOLISM BY 3-METHYLCHOLANTHRENE-INDUCED HAMSTER HEPATIC CYTOCHROME-P-450S

We have studied the activation of aflatoxin B1 by hamster liver microsomes and purified hamster cytochrome P‐450 isozymes using a umu mutagen test. The hamster liver microsomes or S‐9 fractions were much more active than rat liver microsomes or S‐9 fractions in the activation of umu gene expression by aflatoxin B1 metabolites. 3‐Methylcholanthrene treatment increased aflatoxin B1 activation by hamster liver microsomes. Two major 3‐methylcholanthrene‐inducible cytochrome P‐450 isozymes, P‐450 MC1 (IIA) and P‐450 MC4 (IA2), were purified from 3‐methylcholanthrene‐treated hamster liver microsomes, and the metabolism of aflatoxin B1 by these two cytochromes was studied. In the reconstituted enzyme system, both P‐450 MC1 and P‐450 MC4 were highly active in the activation of aflatoxin B1, and antibodies against these P‐450s specifically inhibited these activities. Antibody against P‐450 MC1 inhibited the activation of aflatoxin B1 by 20% in the presence of 3‐methylcholanthrene‐treated hamster liver microsomes. In contrast, antibody against P‐450 MC4 stimulated the activity by 175%. These results indicated that hamster P‐450 MC1 might convert aflatoxin B1 to more toxic metabolite(s), whereas P‐450 MC4 might convert aflatoxin B1 to less toxic metabolite(s), than aflatoxin B1 in liver microsomes. The metabolite(s) produced by both hamster cytochrome P‐450 MC1 and MC4 were genotoxic in the umu mutagen test. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company