Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases
Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases
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DOI：
10.1093/carcin/23.6.1071
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发表时间：
2002-06-01
期刊：
影响因子：
4.7
通讯作者：
Rogan, EG
中科院分区：
文献类型：
--
作者：
Cavalieri, EL;Li, KM;Rogan, EG
儿茶酚雌激素和儿茶酚胺被代谢成醌类，致白血病苯的代谢产物儿茶酚（1，2-二羟基苯）也可被氧化成醌类。我们在这里报告，醌类化合物通过辣根过氧化物酶，酪氨酸酶或苯巴比妥诱导的大鼠肝微粒体的儿茶酚和多巴胺的酶促氧化与DNA反应，通过1，4-Michael加成形成主要的脱嘌呤加合物在N-7的鸟嘌呤和N-3的腺嘌呤。这些加合物类似于通过酶促氧化的4-儿茶酚雌激素与DNA形成的加合物（Cavalieri，E.L.，等人（1997）Proc. Natl Acad.科学，94，10937）。加合物通过与儿茶酚醌或多巴胺醌与脱氧鸟苷或腺嘌呤反应合成的标准加合物进行比较来鉴定。我们假设脱嘌呤位点诱导的突变，由脱嘌呤加合物产生，可能会引发苯和雌激素引起的癌症，以及多巴胺引起的一些神经退行性疾病（如帕金森病）。这些数据表明，有一个统一的分子机制，即在鸟嘌呤的N-7和腺嘌呤的N-3形成特异性脱嘌呤DNA加合物，这可能引发许多癌症和神经退行性疾病。
Catechol estrogens and catecholamines are metabolized to quinones, and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogenic benzene can also be oxidized to its quinone. We report here that quinones obtained by enzymatic oxidation of catechol and dopamine with horseradish peroxidase, tyrosinase or phenobarbital-induced rat liver microsomes react with DNA by 1,4-Michael addition to form predominantly depurinating adducts at the N-7 of guanine and the N-3 of adenine. These adducts are analogous to the ones formed with DNA by enzymatically oxidized 4-catechol estrogens (Cavalieri,E.L., et al. (1997) Proc. Natl Acad. Sci., 94, 10937). The adducts were identified by comparison with standard adducts synthesized by reaction of catechol quinone or dopamine quinone with deoxyguanosine or adenine. We hypothesize that mutations induced by apurinic sites, generated by the depurinating adducts, may initiate cancer by benzene and estrogens, and some neurodegenerative diseases (e.g. Parkinson's disease) by dopamine. These data suggest that there is a unifying molecular mechanism, namely, formation of specific depurinating DNA adducts at the N-7 of guanine and N-3 of adenine, that could initiate many cancers and neurodegenerative diseases.