Formation of benzylic-DNA adducts resulting from 7,12-dimethylbenz[a]anthracene in vivo.
Formation of benzylic-DNA adducts resulting from 7,12-dimethylbenz[a]anthracene in vivo.
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7,12-二甲基苯并[a]蒽在体内形成苄基-DNA 加合物。
DOI：
10.1021/tx049686p
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Gupta,RameshC
中科院分区：
文献类型：
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作者：
RaviKumar,MNV;Vadhanam,ManickaV;Horn,Jamie;Flesher,JamesW;Gupta,RameshC
本文研究了7，12-二甲基苯并[a]蒽及其代谢物在大鼠皮下注射后−加合物的形成。在这里，我们发现7-羟甲基-12-甲基苯并[a]菲(7-HMBA)和7-磺氧甲基-12-甲基苯并[a]菲(7-SMBA)产生了一些与−形成的加合物难以区分的苄基DMBA加合物。加合物的分析采用丁醇富集法-32P-后标记分析。雌性−-Dawley大鼠经420moldmBA/kgb.wt联合给药后，皮下组织中有2个主要加合物和多达9个次要加合物，其层析结果与体外制备的苄基−加合物相似。皮下注射7-HMBA、7-SMBA和7-甲基-12-羟甲基苯并[a]茂(12-HMBA)(分别为2 10、42和2 10μ/kg b.wt)，均可形成一个主要的和几个次要的−加合物。通过与参考加合物的共层析，得出结论：来自母体化合物的苄基DNA加合物4与7-HMBA和7-SMBA的主要加合物共迁移，而加合物2和3分别与12-HMBA和7-甲基-12-磺氧甲基苯并[a]菲的加合物共迁移。这些数据表明，7-磺氧甲基和12-磺氧甲基衍生物产生不同的加合物。还检测到了几个主要和次要的与二醇环氧化物相关的DNA加合物。二元醇环氧化物−和苄基−加合物的比例为2：1。口服、腹膜和乳房注射DMBA后24小时，肝脏和乳腺中未检测到苯基加合物，而SMBA和/或HMBA可明显形成加合物，提示DMBA羟化生成HMBA可能是O-甲基取代途径的限速步骤。本研究清楚地证明了二甲基丁二酸二苯甲酯在体内形成−加合物。数据还揭示了DMBA的12-甲基参与了加合物的形成。
Studies were undertaken to determine the formation of benzylic−DNA adducts in rats administered 7,12-dimethylbenz[a]anthracene (DMBA) and itsmeso-region metabolites by subcutaneous injection. Here, we show that 7-hydroxymethyl-12-methylbenz[a]anthracene (7-HMBA) and 7-sulfoxymethyl-12-methylbenz[a]anthracene (7-SMBA) gave rise to some benzylic−DNA adducts indistinguishable from adducts formed from DMBA. Adducts were analyzed by butanol enrichment-mediated32P-postlabeling assay. Female Sprague−Dawley rats given a combined dose of 420 μmol DMBA/kg b. wt resulted in two major and up to nine minor adducts in the subcutaneous tissue, with chromatographic resemblance to benzylic−DNA adducts prepared in vitro. Subcutaneous administration of 7-HMBA, 7-SMBA, and 7-methyl-12-hydroxymethylbenz[a]anthracene (12-HMBA) (210, 42, and 210 μmol/kg b. wt, respectively) each resulted in one major and several minor benzylic−DNA adducts. From cochromatography with reference adducts, it was concluded that the benzylic DNA adduct 4, derived from the parent compound, comigrates with the major adduct from 7-HMBA and 7-SMBA, whereas adducts 2 and 3 comigrate with adducts resulting from 12-HMBA and 7-methyl-12-sulfooxymethylbenz[a]anthracene, respectively. These data suggest that 7-sulfooxymethyl- and 12-sulfooxymethy derivatives produce distinct adducts. Several major and minor diol epoxide-related DNA adducts were also detected. The diol epoxide− and benzylic−DNA adducts were found in a 2:1 ratio. The oral, intraperitoneal, and intramammiliary treatments with DMBA showed no detectable benzylic adducts in the liver and mammary glands 24 h after the last treatment, although the adduct formation was clearly evident with SMBA and/or HMBA treatments, suggesting that hydroxylation of DMBA to form HMBA may be the rate-limiting step for themeso-methyl substitution pathway. The present study clearly demonstrates the in vivo formation of benzylic−DNA adducts from DMBA. The data also reveal the involvement of the 12-methyl group of DMBA in adduct formation.