Cytochrome P450 decreases are correlated to increased microsomal oxidativedamage in rabbit liver and primary cultures of rabbit hepatocytes exposed to AFB1

Although numerous studies report hepatic drug metabolizing enzyme alteratio ns during aflatoxicosis, the mechanisms involved in P450 decreases remain t o be established. The purpose of this work is to investigate whether increa sed oxidative damage revealed by the detection of malondialdehyde (MDA), li pofuscin substances, and conjugated dienes in microsomes, could explain the decreased P450 content. Studies were conducted with two different doses of aflatoxin B1 (AFB1), both in vivo in rabbits and ex vivo in primary cultur es of rabbit hepatocytes, in the presence or absence of beta-naphthoflavone or rifampicin used as respective P450 inducers. Strong negative correlatio ns were observed between MDA and P450 contents, both in vivo and ex vivo, w hereas rifampicin appears to protect the hepatocytes from oxidative damage but not AFB1 toxicity. Positive correlation were also obtained between MDA formation and lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT ) or alanine aminotransferase (ALAT) releases, used as non-specific markers of AFB1 toxicity. Taken together these results suggest that the dramatic d ecreases of cytochrome P450 observed in vivo during aflatoxicosis could be linked, at least in part, to microsomal oxidative damage. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.