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© 1987 Oxford University Press

research-article

Suiphotransferase-mediated covalent binding of the carcinogen 7,12-dihydroxymethylbenz to calf thymus DNA and its inhibition by glutatbione transferase

Tadashi Watabe 1, Akira Hiratsuka and Kenichiro Ogura

Laboratory of Drug Metabolism and Toxicology, Department of Hygienic Chemistiy, Tokyo College of Pharmacy 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-03, Japan

1whom reprint requests should be sent

The carcinogen, 7,12-dihydroxymethylbenz[a]anthracene (DHBA), bound covalently through its 7-methylene carbon to calf thymus DNA via DHBA 7-sulphate, a regiospecifical-ly formed, reactive metabolite, when incubated with rat liver cytosol in the presence of 3'-phosphoadenosine 5'-phospho-sulphate (PAPS). The hydroxysteroid sulphotransferase in hibitor, dehydroepiandrosterone sulphate, strongly retarded the covalent binding of DHBA to DNA as well as the DHBA 7-sulphate formation from DHBA in the biological system, while pentachlorophenol and dichloronitrophenol showed little effect on these reactions. DHBA 7-sulphate was a good sub-strate for rat liver cytosolic glutathione (GSH) transferases, so that the PAPS-dependent covalent binding of DHBA to DNA could be markedly retarded in the presence of GSH with concomitant formation of a significant amount of the stable conjugate, S-(12-hydroxymethylbenz[a]anthracen-7-yl)meth-ylgiutathione. From DNA, incubated with DHBA in the pres ence of the hepatic cytosol and PAPS as well as with DHBA 7-sulphate alone, two purine base adducts were isolated after hydrolysis. The purine base adducts accounted for 70% of the total covalent binding of the carcinogen or its 7-sulphate to the nucleic acid and were identified with synthetic speci mens as N6(12-hydroxymethlbenz[a]anthracen-7-yl)-methylguanine. The ratio of the adenine to guanine adducts was 1:2.5 with DNA, incubated with DHBA in the presence of hepatic cytosol and PAPS as well as with various concen-trations of DHBA 7-sulphate.


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