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7-suffooxymethyl-12-methylbenz[a]anthracene is an electrophilic mutagen, but does not appear to play a role in carcinogenesis by 7,12-dimethylbenz[a]anthracene or 7-hydroxymethyl-12-methylbenz[a]anthracene

Cited 32 time in Web of Science Cited 35 time in Scopus
Authors
Surh, Young-Joon; Leim, Amy; Miller, Elizabeth C.; Miller, James A.
Issue Date
1991-02
Citation
Carcinogenesis, Vol.12 No.2, pp.339-347
Abstract
Although a bay-region dihydrodiolepoxide metabolite has been considered as a principal ultimate electrophilic and carcinogenic form of 7,12-dimethylbenz[alpha]anthracene (DMBA), other reactive metabolites might also play a role in the activation of this hydrocarbon in vivo. Earlier studies suggested the hydroxylation of a meso-anthracenic methyl group with subsequent formation of a benzylic ester bearing a good leaving group (e.g. sulfate) as a metabolic activation pathway for DMBA. In support of this hypothesis, the formation of an electrophilic and mutagenic sulfuric acid ester of 7-hydroxymethyl-12-methylbenz[alpha]anthracene (HMBA) by rat liver cytosolic sulfotransferase activity has previously been demonstrated, but no data have been reported on the carcinogenicity of this reactive ester. In the present study, we compared the carcinogenicity of chemically synthesized sodium 7-sulfooxymethyl-12-methylbenz[alpha]anthracene (SMBA) with that of the parent methyl and hydroxymethyl hydrocarbons. For this purpose, tests were made in several animal tumor models: induction of hepatomas in male B6C3F1 mice, lung adenoma induction in A/J mice, initiation of mouse skin tumors, development of sarcomas in rats at the injection sites, and initiation of preneoplastic enzyme-altered foci in rat liver. Data from all of these studies indicate that SMBA is not more carcinogenic than DMBA or HMBA. In addition, the carcinogenic activity of HMBA was not altered by dehydroepiandrosterone, a strong inhibitor of sulfotransferase activity for HMBA. DMBA produced only a low level of hepatic benzylic DNA adducts in rats when a relatively high dose was administered. These adducts constitute < 5% of total DMBA residues bound to hepatic DNA. The rest of the adducts appear to be associated with other electrophilic intermediates including the dihydrodiol epoxide metabolites. Based on the results of our present study, it is unlikely that DMBA exerts its carcinogenic activity via metabolic activation to SMBA.
ISSN
0143-3334
URI
https://hdl.handle.net/10371/172688
DOI
https://doi.org/10.1093/carcin/12.2.339
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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