Metabolism and covalent binding to DNA of 7-methylbenzo(a)pyrene.
The ultimate carcinogenic form of benzo(a)pyrene (BP) is thought to result from metabolic activation at the 7 to 10 positions. Substitution by a methyl group at these positions would be expected to inhibit strongly their metabolism even though 7-methylbenzo(a)pyrene (7-MeBP) has been reported to be carcinogenic in some tumor models. The metabolism of 7-MeBP was, therefore, studied using both microsomal preparations and whole cells, the products being analyzed by high-pressure liquid chromatography, fluorescence spectrophotometry, and mass spectrometry. These studies revealed that many of the expected metabolites were formed by microsomes, but in addition 7-MeBP yielded a compound which was isolated and identified as trans-7,8-dihydro-7,8-dihydroxy-7-methylbenzo(a)pyrene. These results indicate that, despite the presence of a methyl group at the 7 position, a substituted BP can undergo the same initial metabolic activation as BP itself. However, in contrast to BP, the 7,8-dihydrodiol formed from 7-MeBP was almost racemic, and neither enantiomer was very active in the Ames bacterial mutagenesis assay when compared with trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene. The metabolism of 7-MeBP was also studied in 10T1/2 cells. The hydrocarbon was metabolized readily and bound to DNA of the cells to about one-eighth of the level found for BP. However, no 7,8-dihydro-7,8-dihydroxy-7-methylbenzo(a)pyrene could be detected in the culture medium.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects
D001580:Benzopyrenes; C032121:7-methylbenzo(a)pyrene; D004247:DNA