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Sulfotransferase-mediated Activation of 4-Hydroxy- and 3,4-Dihydroxy-3,4-dihydrocyclopenta[c,d]pyrene, Major Metabolites of Cyclopenta[c,d]pyrene¹

Division of Toxicology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Cyclopenta[c,d]pyrene, a ubiquitous environmental and occupational pollutant, has been reported to be metabolically activated through epoxidation at the 3,4 double bond in the cyclopenta ring to produce an electrophilic and mutagenic cyclopenta[c,d]pyrene-3,4-epoxide. 4-Hydroxy-3,4-dihydrocyclopenta[c,d]-pyrene (4-HDCPP) and 3,4-dihydroxy-3,4-dihydrocyclopenta[c,d]pyrene (3,4-DHDCPP) are known to be major metabolites of cyclopenta[c,d]pyrene, which appear to be derived from cyclopenta[c,d]pyrene-3,4-epoxide. The present study was undertaken to determine whether 4-HDCPP or 3,4-DHDCPP can be further activated via the formation of reactive benzylic sulfuric acid ester metabolites. Thus, when 4-HDCPP or 3,4-DHDCPP was incubated with calf thymus DNA in the presence of rodent liver cytosol and the sulfo group donor, 3'-phosphoadenosine-5'-phosphosulfate, a significant covalent DNA binding was observed. This cytosol- and 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding was inhibited by 2,6-dichloro-4-nitrophenol and dehydroepiandrosterone, suggesting the involvement of both phenol and hydroxysteroid sulfotransferases in the activation of 4-HDCPP and 3,4-DHDCPP. A gender difference was observed for the hepatic cytosolic sulfotransferase activity for 4-HDCPP in rats (i.e., male > female). Of the two isomers of 3,4-DHDCPP, the trans-diol produced DNA adducts to a much greater extent than did the cis counterpart by sulfotransferase. 4-HDCPP and 3,4-DHDCPP were also mutagenic toward bacteria in the presence of hepatic cytosol and 3'-phosphoadenosine-5'-phosphosulfate. The chemically synthesized sulfuric acid ester 4-sulfooxy-3,4-DCPP was directly mutagenic without any activation system. The data from this study suggest that sulfotransferase plays an important role in the activation of those secondary benzylic hydroxyl metabolites derived from cyclopenta[c,d]pyrene-3,4-epoxide and, possibly, from epoxides of other aromatic hydrocarbons.

¹ Supported in full by National Institute of Environmental Health Services Grants ES 02109 and ES 01640.

² Present address: Division of Environmental Health Sciences, LEPH, Yale University School of Medicine, 60 College Street, New Haven, CT 06510.

³ To whom requests for reprints should be addressed, at Department of Chemistry and Division of Toxicology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139.

Received 9/ 3/92. Accepted 12/22/92.

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