METABOLIC-ACTIVATION OF METHYL-HYDROXYLATED DERIVATIVES OF 7,12-DIMETHYLBENZ[A]ANTHRACENE BY HUMAN LIVER DEHYDROEPIANDROSTERONE-STEROID SULFOTRANSFERASE

Methyl-hydroxylated metabolites of the potent carcinogen, 7,12-dimethy lbenz[a]anthracene (DMBA), namely, 7-hydroxymethyl- 12-methylbenz[a] a nthracene (7-OH-DMBA), 7-methyl-12-hydroxymethylbenz[a]anthracene (12- OH-DMBA) and 7,12-dihydroxymethylbenz[a]anthracene (7,12-diOH-DMBA), w ere examined as substrates for sulfotransferase bioactivation in diffe rent human tissue cytosols, Hepatic cytosols, which were able to catal yze the 3'-phosphoadenosine 5'-phosphosulfate (PAPS)-dependent DNA bin ding of 7-OH-DMBA, 12-OH-DMBA and 7,12-diOH-DMBA, were highly sensitiv e to inhibition by dehydroepiandrosterone (DHEA), a specific substrate for human DHEA-steroid sulfotransferase (IC50 = 5 mu M), By compariso n, 2,6-dichloro-4-nitrophenol, a potent inhibitor of the thermostable (TS)-phenol and estrogen sulfotransferases, did not have an appreciabl e inhibitory effect. Neither p-nitrophenol, a high affinity substrate for human TS-phenol and estrogen sulfotransferases, nor dopamine, a sp ecific substrate for the thermolabile (TL)-phenol sulfotransferase, si gnificantly inhibited the DNA binding of 12-OH-DMBA catalyzed by hepat ic cytosols, Inter-subject variation (n = 12) of the PAPS-dependent DN A 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 wa s not detected in cytosols from human colon, pancreas, larynx or mamma ry gland. Both TS- and TL-phenol sulfotransferases were active in huma n liver and colon but only liver contained DHEA-sulfotransferase activ ity, These results indicate that the sulfotransferase-mediated activat ion of the methylhydroxylated DMBAs is predominantly catalyzed by DHEA -steroid sulfotransferase in human liver and that TS- and TL-phenol su lfotransferases and estrogen sulfotransferase are not involved in the catalysis.