Dose-related effect of aflatoxin B1 on liver drug metabolizing enzymes in rabbit

Toxicology. 1996 Apr 15;108(1-2):39-48. doi: 10.1016/s0300-483x(95)03269-l.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aflatoxin B1 / administration & dosage
  • Aflatoxin B1 / toxicity*
  • Animals
  • Blotting, Western
  • Body Weight / drug effects
  • Carcinogens / administration & dosage
  • Carcinogens / toxicity*
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Glutathione Transferase / drug effects
  • Glutathione Transferase / metabolism
  • Liver / drug effects*
  • Liver / enzymology*
  • Male
  • Microsomes, Liver / metabolism
  • Organ Size / drug effects
  • Rabbits

Substances

  • Carcinogens
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Aflatoxin B1
  • Glutathione Transferase