Metabolic activation of cyclopenta(cd)pyrene to 3,4-epoxycyclopenta(cd)pyrene by rat liver microsomes.
Cyclopenta(cd)pyrene (CPP), a polycyclic aromatic hydrocarbon without a bay region, is a potent bacterial mutagen. The experiments reported in this paper demonstrate that the major CPP metabolite generated by liver microsomes prepared from either phenobarbital or 3-methylcholanthrene pretreated rats is the optically active trans-3,4-dihydroxy-3,4-dihydrocyclopenta(cd)pyrene. Other experiments indicate that formation of the trans-3,4-dihydrodiol of CPP probably proceeds via enzymatic hydrolysis of 3,4-epoxycyclopenta(cd)pyrene by opening of the O--C(3) bond. (a) The racemic 3,4-epoxycyclopenta(cd)pyrene has been synthesized via the bromohydrin of CPP and shown to hydrolyze primarily to 3,4-dihydrocyclopenta(cd)pyrene-4-one and to mixtures of the trans- and cis-3,4-dihydrodiols. Detection of 3,4-dihydrocyclopenta(cd)pyrene-4-one as the major acid catalyzed rearrangement product indicates the opening of the epoxide at the C(3) position to yield a carbonium ion followed by an NIH shift. (b) The synthetic epoxide is potently mutagenic to bacteria with a similar spectrum of mutagenicity against Salmonella typhimurium strains carrying base-pair substitution or frameshift mutations as was seen with CPP in the presence of liver enzymes. These results indicate that 3,4-epoxycyclopenta(cd)pyrene is the major microsomal and mutagenic metabolite of CPP.
D000818:Animals; D003517:Cyclopentanes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D010084:Oxidation-Reduction; D011721:Pyrenes / Q000096:biosynthesis* / Q000378:metabolism*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D009153:Mutagens; D011721:Pyrenes; C016328:cyclopenta(c,d)pyrene; C029268:3,4-dihydroxy-3,4-dihydrocyclopenta(cd)pyrene; C027599:cyclopenta(cd)pyrene 3,4-oxide