Journal Article

Metabolic activation of methyl-hydroxylated derivatives of 7,12-dimethylbenz[a]anthracene by human liver dehydroepiandrosterone-steroid sulfotransferase.

H C Chou, S Ozawa, P P Fu, N P Lang and F F Kadlubar

in Carcinogenesis

Volume 19, issue 6, pages 1071-1076
Published in print June 1998 | ISSN: 0143-3334
Published online June 1998 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/19.6.1071
Metabolic activation of methyl-hydroxylated derivatives of 7,12-dimethylbenz[a]anthracene by human liver dehydroepiandrosterone-steroid sulfotransferase.

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Methyl-hydroxylated metabolites of the potent carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), namely, 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OH-DMBA), 7-methyl-12-hydroxymethylbenz[a]anthracene (12-OH-DMBA) and 7,12-dihydroxymethylbenz[a]anthracene (7,12-diOH-DMBA), were examined as substrates for sulfotransferase bioactivation in different human tissue cytosols. Hepatic cytosols, which were able to catalyze the 3'-phosphoadenosine 5'-phosphosulfate (PAPS)-dependent DNA binding of 7-OH-DMBA, 12-OH-DMBA and 7,12-diOH-DMBA, were highly sensitive to inhibition by dehydroepiandrosterone (DHEA), a specific substrate for human DHEA-steroid sulfotransferase (IC50 = 5 microM). By comparison, 2,6-dichloro-4-nitrophenol, a potent inhibitor of the thermostable (TS)-phenol and estrogen sulfotransferases, did not have an appreciable inhibitory effect. Neither p-nitrophenol, a high affinity substrate for human TS-phenol and estrogen sulfotransferases, nor dopamine, a specific substrate for the thermolabile (TL)-phenol sulfotransferase, significantly inhibited the DNA binding of 12-OH-DMBA catalyzed by hepatic cytosols. Inter-subject variation (n = 12) of the PAPS-dependent DNA binding of 12-OH- and 7,12-diOH-DMBAs also correlated well with DHEA-sulfotransferase activity (r = 0.90; P < 0.00001 and r = 0.92; P < 0.00001, respectively). This sulfation-dependent metabolic activation was not detected in cytosols from human colon, pancreas, larynx or mammary gland. Both TS- and TL-phenol sulfotransferases were active in human liver and colon but only liver contained DHEA-sulfotransferase activity. These results indicate that the sulfotransferase-mediated activation of the methyl-hydroxylated DMBAs is predominantly catalyzed by DHEA-steroid sulfotransferase in human liver and that TS- and TL-phenol sulfotransferases and estrogen sulfotransferase are not involved in the catalysis.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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