METABOLIC-ACTIVATION OF CYCLOPENTA(CD)PYRENE TO 3,4-EPOXYCYCLOPENTA(CD)-PYRENE BY RAT-LIVER MICROSOMES

Abstract

Cyclopenta(cd)pyrene (CPP), a polycyclic aromatic hydrocarbon without a bay region, is a potent bacterial mutagen. The major CPP metabolite generated by liver microsomes prepared from 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. The racemic 3,4-epoxycyclopenta(cd)pyrene was 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. 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. 3,4-Epoxycyclopenta(cd)pyrene is the major microsomal and mutagenic metabolite of CPP. [CPP is a weak tumor initiator.].