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Metabolic Activation of Cyclopenta(cd)pyrene to 3,4-Epoxycyclopenta(cd)pyrene by Rat Liver Microsomes¹

Laboratory of Toxicology, Department of Physiology [A. G., E. E.], and Department of Microbiology [E. E.], Harvard School of Public Health, Boston, Massachusetts 02115

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.

¹ Supported by Grant ES-02021 from the National Institute of Environmental Health Sciences.

² Present address: Department of Environmental Sciences and Engineering, University of North Carolina, School of Public Health, Chapel Hill, N. C. 27514.

³ To whom requests for reprints should be addressed, at Department of Microbiology, Harvard School of Public Health, 665 Huntington Avenue, Boston, Mass. 02115.

Received 2/14/80. Accepted 7/22/80.