Effects of phenobarbital on the biliary excretion of aflatoxin P1-glucuronide and aflatoxin B1-S-glutathione in the rat.
Direct h.p.l.c. analysis of bile separated at least five major water-soluble metabolites of AFB; the two most prevalent AFB metabolites were identified as AFB-S-glutathione (AFB-GSH) and AFP1-glucuronide, which accounted for 49-57% and 4-15% of total biliary AFB metabolites, respectively. In the two hours following AFB administration, phenobarbital-treated rats eliminated 50% more AFB-derived radioactivity in bile compared with controls. No qualitative differences in the profile of biliary AFB metabolites were noted between phenobarbital-treated and control rats. However, a 90% increase in the rate of excretion of AFB-GSH was found in phenobarbital-treated animals. Phenobarbital treatment had no significant effect on the amount of AFB remaining in the liver after two hours, but decreased the amount of AFB covalently bound to hepatic DNA by 55%. When individual animals from both control and phenobarbital-treated groups were considered, the correlation between the increase in excretion of AFB-GSH and the decrease in covalent binding was significant with a correlation coefficient of 0.77. This finding is consistent with the hypothesis that induction of GSH S-transferase is responsible for the anticarcinogenic effects of phenobarbital towards AFB-induced hepatocarcinogenicity, although changes in the rate of formation of aflatoxin P1 or other biotransformation pathways may also be important.
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000348:Aflatoxins; D005965:Glucuronates; C042410:aflatoxin P1; D004247:DNA; D016604:Aflatoxin B1; D005978:Glutathione; D010634:Phenobarbital