Dose-related effect of aflatoxin B1 on liver drug metabolizing enzymes in rabbit.
The effects of chronic administration of aflatoxin B1 (AFB1) on liver drug metabolism enzymes were measured in New Zealand rabbits divided into three groups of 5 animals, each receiving over 5 days either arabic gum or AFB1 in arabic gum at a daily oral dose of 0.05 or 0.10 mg/kg. These treatments did not lead to any lethality in any of the treated groups, but the body weight gain was altered. Biochemical exploration of plasma components revealed a dose-dependent hepatotoxicity characterized by cytolysis and cholestasis. At 0.10 mg/kd/day of AFB1, significant decreases were observed in total liver microsomal cytochrome P450, several P450-dependent monooxygenase activities, all individual P450 isoenzymes levels analysed by Western-blotting and glutathione S-transferase activities. By contrast, at 0.05 mg/kg/day of AFB1, even though total cytochrome P450 was decreased by 30%, only P450 1A1 and 3A6 isoenzymes, and aniline hydroxylation, pentoxyresorufin O-depentylation, aminopyrine, erythromycin, ethylmorphine and dimethylnitrosamine N-demethylations were affected. In the same animal group, the only glutathione S-transferase accepting CDNB (1-chloro-2,4-dinitrobenzene) as substrate was decreased by 22%. UDP-glucuronyltransferase accepting p-nitrophenol as substrate was increased in both groups of animals (33-62%). The mechanisms that could contribute to the observed changes in drug metabolizing enzymes are discussed.
Guerre
P
P
Unité associée I.N.R.A. de Physiopathologie et Toxicologie expérimentales, E.N.V.T., Toulouse, France.
Eeckhoutte
C
C
Larrieu
G
G
Burgat
V
V
Galtier
P
P
D000284:Administration, Oral; D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits
D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D005982:Glutathione Transferase