Carcinogenesis, Vol 19, 1071-1076, Copyright © 1998 by Oxford University Press
HC Chou, S Ozawa, PP Fu, NP Lang and FF Kadlubar
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.
ARTICLES
Metabolic activation of methyl-hydroxylated derivatives of 7,12- dimethylbenz[a]anthracene by human liver dehydroepiandrosterone-steroid sulfotransferase
National Center for Toxicological Research (HFT-100), Jefferson, AR 72079, USA.
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