title: Glucuronide conjugation reduces the cytotoxicity but not the mutagenicity of benzo(a)pyrene in the CHO/HGPRT assay.
abstract: Benzo(a)pyrene (B[a]P) is biotransformed by the mixed-function oxidase (MFO) system to numerous metabolites some of which are cytotoxic and/or mutagenic to mammalian cells. However, conjugation of B(a)P metabolites with glucuronic acid in vivo is a major pathway of detoxication and elimination. The effects of glucuronide conjugation on B(a)P-induced cytotoxicity and mutagenicity were studied using the CHO/HGPRT assay with a rat liver homogenate preparation containing MFO system cofactors (S9 mix) and uridine diphosphate alpha-D-glucuronic acid (UDPGA). B(a)P metabolites proximate to the biologically active B(a)P quinones (B[a]P 6-OH) and to the B(a)P 7,8-diol-9,10 epoxide isomers (B[a]P 7,8-diol), were also assayed with S9 mix in the absence and presence of UDPGA. The addition of UDPGA to S9 mix reduced B(a)P-induced cytotoxicity but did not affect mutagenicity. B(a)P 6-OH-mediated cytotoxicity was also reduced in the presence of UDPGA. UDPGA had no effect on B(a)P 7,8-diol-induced cytotoxicity or mutagenicity. B(a)P phenols have been shown to be the preferred B(a)P-metabolite substrates for UDP-glucuronyltransferase enzymes. Thus, the reduction of B(a)P and B(a)P 6-OH-induced cytotoxicity by glucuronide conjugation is likely due to the elimination of cytotoxic phenols and quinones. Since B(a)P 7,8-diol is a poor substrate for UDP-glucuronyltransferase enzymes, no effects on B(a)P-induced mutagenicity or B(a)P 7,8-diol-induced cytotoxicity and mutagenicity were observed.
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D020723:Glucuronic Acid; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009154:Mutation / Q000187:drug effects*; D010053:Ovary; D013329:Structure-Activity Relationship
chemical_list: D005965:Glucuronates; D001564:Benzo(a)pyrene; D020723:Glucuronic Acid; D006899:Mixed Function Oxygenases