Effects of aflatoxin B 1 on the activity of drug-metabolizing enzymes in rat liver

Abstract

Aflatoxin B 1 (AFB 1) is one of the most active hepatotoxic and hepatocarcinogenic compounds known for rats. In order to evaluate the mechanism of action of the toxin on the liver, the effects of aflatoxin B 1 on the enzymes involved in its transformation, such as the monooxygenase-cytochromes P-450-dependent and conjugating enzymes, were studied. At the same time, liver damage was determined by measuring the activities of plasma γ-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) as well as the concentration of bilirubin. Male Sprague-Dawley rats received a single ip dose of AFB 1 (1 or 3 mg/kg). The effects of the toxic compound on the activity of drug-metabolizing enzymes were followed 20 days after this single exposure. Mortality (18%) within 7 days following administration was produced only by the higher dose. The same dose also significantly decreased the total level of hepatic proteins and impaired the activity of aminopyrine N-demethylase. AFB 1 lowered the content of cytochromes P-450 by 32 and 69% at the 1 and 3 mg/kg dose levels, respectively. Epoxide hydrase activity was increased by 121 and 170% at 1 and 3 mg/kg, respectively, whereas UDP-glucuronyltransferase activity was increased (44%) at 1 mg/kg, but also decreased at the same extent for the higher dose. The activity of GSH S-epoxide transferase was decreased by a maximum of 53% by 3 mg/kg AFB 1. Results obtained by the 3rd day following the administration of 3 mg/kg AFB 1 showed that blood levels of all the factors studied in this experiment were increased above control values, while at lower dose of AFB 1 (1 mg/kg), only the activities of AST and ALT were significantly increased. The activities of these enzymes were 27 to 42 times greater in rats treated with 3 mg/kg AFB 1 than in rats given 1 mg/kg AFB 1. Most of the biological features studied tended to return to control values between the 9th and 20th day after AFB 1 treatment. This study makes it possible to compare changes in tissue levels of drug-metabolizing enzymes at two doses of AFB 1. It can also be used to demonstrate any time lag or differing behavior of the serum enzymes, notably the sensibility of transaminases.