Oxidation and DNA binding of (+)-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene in mouse epidermis in vivo and effects of coadministration of catechol.
Using a stereochemical probe as described by Marnett (Carcinogenesis (Lond.), 8: 1365-1373, 1987), we have investigated the mechanism of oxidation of (+)-[3H]BaP-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene [(+)-[3H]BaP-7,8-diol] in mouse epidermis in vivo. Groups of mice were topically treated with (+)-[3H]BaP-7,8-diol (60 nmol/mouse) and sacrificed at intervals from 1/2 to 8 h post treatment. (-)-Anti- and (+)-syn-7,8-[3H]dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) were formed as metabolites in a ratio of about 4 to 1, respectively, as determined by HPLC analysis of the hydrolysis products. Pretreatment of mice with indomethacin, an inhibitor of prostaglandin H synthase, did not alter the ratio of anti- to syn-BPDE-derived hydrolysis products. Pretreatment of mice with the cytochrome P-450 inducer, beta-naphthoflavone, yielded twice the level of syn-[3H]BPDE in mouse skin at the 1/2-h survival point. However, this enhancing effect diminished over time. Coadministration of 1,2-dihydroxybenzene (catechol) with (+)-[3H]BaP-7,8-diol decreased the formation of (-)-anti-[3H]BPDE and also decreased lipid peroxidation, as measured by the extent of formation of thiobarbituric acid-reactive material in mouse epidermis. Analysis of mouse epidermal DNA adducts 24 h after topical application (+)-[3H]BaP-7,8-diol indicated that the major adduct is not formed from the major metabolite (-)-anti-BPDE. Acid hydrolysis of the major adduct resulted in the formation of a small amount of r-7,c-9,c-10,t-8-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene and two unidentified products different from 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydro-BaP. Coadministered catechol suppressed the formation of this adduct by 30%. The present observation suggests that a peroxyl radical-mediated epoxidation pathway is involved in the oxidation of (+)-[3H]BaP-7,8-diol in mouse skin in vivo.
Melikian
A A
AA
American Health Foundation, Valhalla, New York 10595.
Bagheri
K
K
Hoffmann
D
D
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction; D014316:Tritium
D002273:Carcinogens; D002396:Catechols; D004101:Dihydroxydihydrobenzopyrenes; D014316:Tritium; C015813:4,5-dihydroxy-4,5-dihydrobenzo(a)pyrene; D004247:DNA; C034221:catechol; D007213:Indomethacin