Release of mutagenic metabolites of benzo[a]pyrene from the perfused rat liver after inhibition of glucuronidation and sulfation by salicylamide.
The role of glucuronide and sulfate conjugation in presystemic inactivation of benzo[a]pyrene (BP) metabolites was investigated with rat livers perfused with BP (12 mumol). Comparisons were made between metabolite profiles and mutagenicity of medium from perfusions with and without salicylamide, a selective inhibitor of glucuronide and sulfate conjugation. After 4 h perfusion in the presence of salicylamide, certain BP metabolites (diols, quinones, phenols, and metabolites more polar than BP-9,10-diol) were significantly increased at the expense of quinones and phenols in the glucuronide fraction. Mutagenicity of medium (detected by the Ames test, using tester strains TA98 and TA100) was low in perfusion without salicylamide. Mutagenicity detected with tester strain TA98 was significantly increased in perfusions with salicylamide. Involvement of glucuronidation in BP inactivation was also observed at the subcellular level; when cofactors of glucuronidation were added to liver homogenates along with the NADPH regenerating system in the Ames test, BP mutagenicity was markedly decreased. Both the activation of BP to mutagenic metabolites and the inactivation of BP metabolites by glucuronidation was much more pronounced with liver homogenates from 3-methylcholanthrene-treated rats than with those from phenobarbital-treated animals or untreated controls. The results suggest an important role for glucuronidation and sulfation in the inactivation and elimination of polycyclic aromatic hydrocarbons.
D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009153:Mutagens; D051381:Rats; D011919:Rats, Inbred Strains; D012457:Salicylamides / Q000494:pharmacology*; D013431:Sulfates / Q000378:metabolism
D001580:Benzopyrenes; D002273:Carcinogens; D005965:Glucuronates; D009153:Mutagens; D012457:Salicylamides; D013431:Sulfates; D001564:Benzo(a)pyrene; C031060:salicylamide