Age- and sex-related differences in activation of the carcinogen 7-hydroxymethyl-12-methylbenz[a]anthracene to an electrophilic sulfuric acid ester metabolite in rats. Possible involvement of hydroxysteroid sulfotransferase activity.
Metabolic activation of 7-hydroxymethyl-12-methylbenz[a]anthracene (HMBA) and related hydroxymethyl polycyclic aromatic hydrocarbons to electrophilic and mutagenic sulfuric acid esters has been demonstrated previously (Watabe et al., In: Xenobiotic Metabolism and Disposition (Eds. Kato R, Estabrook RW and Cayen MN), pp. 393-400. Taylor & Francis, London, 1989). In the present study, the rat hepatic sulfotransferase activity catalyzing the formation of such reactive sulfuric acid esters was inhibited strongly by dehydroepiandrosterone, a typical substrate hydroxysteroid sulfotransferases (HSSTs). Pentachlorophenol, a potent phenol sulfotransferase inhibitor, had little effect in this regard. A marked sex difference was observed for the hepatic cytosolic sulfotransferase activity for HMBA in rats. This sex difference was age-related; no significant difference was observed in preweanling rats, whereas in adult rats female rat liver showed a much higher enzyme activity. These age- and sex-related differences in the sulfonation of HMBA reflect the regulation of HMBA sulfotransferase activity by gonadal hormones as previously demonstrated with HSSTs. Thus, pretreatment with estradiol benzoate significantly enhanced the sulfotransferase activity for HMBA in both male and female rats, (P less than 0.01 and P less than 0.05 respectively), whereas testosterone propionate pretreatment decreased this activity. Castration of male rats increased the HMBA sulfotransferase activity 2- to 3-fold compared with that in control animals. By contrast, ovariectomy reduced the enzyme activity 38% in females. These results imply that rat liver HSST activity is responsible for the sulfonation of HMBA. Intraperitoneal injection of HMBA (0.25 mumol/g body wt) into infant rats produced benzylic DNA adducts in the liver which were chromatographically identical with those obtained from incubations of HMBA with deoxyguanosine and deoxyadenosine in the presence of hepatic cytosolic sulfotransferase activity. Intraperitoneal administration of sodium 7-sulfooxymethyl-12-methylbenz[a]anthracene resulted in much higher levels of these adducts and the deoxycytidine adduct in the liver DNA than did an equimolar amount of the parent hydroxymethyl hydrocarbon. The levels of hepatic benzylic DNA adducts formed from HMBA were reduced markedly by pretreatment of rats with dehydroepiandrosterone, a strong inhibitor of hepatic sulfotransferase activity for this hydrocarbon.
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McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706.
Liem
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Miller
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Miller
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D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism* / Q000031:analogs & derivatives; D000367:Age Factors; D000818:Animals; D001711:Biotransformation; D002369:Castration; D003687:Dehydroepiandrosterone / Q000008:administration & dosage; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010416:Pentachlorophenol / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D015238:Sulfotransferases; D013466:Sulfurtransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology
D013739:Testosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol; C018970:7-hydroxymethyl-12-methylbenz(a)anthracene; D015127:9,10-Dimethyl-1,2-benzanthracene; C033702:7-(hydroxymethyl)-12-methylbenz(a)anthracene sulfate ester; D010416:Pentachlorophenol; D013466:Sulfurtransferases; D015238:Sulfotransferases; C028152:alcohol sulfotransferase