Metabolic activation of benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and the inhibitory effect of glutathione and cysteine.
Metabolic activation of benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and the inhibitory effect of glutathione and cysteine.
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苯并[a]芘-7,8-二氢二醇和苯并[a]芘-7,8-二氢二醇-9,10-环氧化物对蛋白质结合产物的代谢激活以及谷胱甘肽和半胱氨酸的抑制作用。
DOI：
10.1093/carcin/5.2.199
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发表时间：
1984
期刊：
影响因子：
4.7
通讯作者：
Martinez,M
中科院分区：
文献类型：
--
作者：
Jernström,B;Dock,L;Martinez,M
反式-7，8-二羟基-7，8-二氢苯并(A)芘(BP-7，8-diol)和反式-7，8-二羟基-9，10-环氧基-7，8，9，10-四氢苯并(A)芘(BPDE)的反式异构体(BPDE)被3-甲基胆蒽(MC)处理的大鼠的微粒体激活为与微体蛋白共价结合的活性中间体。还原型谷胱甘肽(GSH)或半胱氨酸的存在显著降低了结合的程度。对BP-7，8-二醇和BPDE在GSH或半胱氨酸存在下微粒体活化后产物的荧光光谱研究表明，形成了具有独特荧光性质的共同反应中间体。细胞色素P448参与了BP-7，8-二醇和BPDE对蛋白质结合产物的激活，这是因为细胞色素P448对NADPH的需求和α-萘黄酮几乎完全抑制。此外，MC处理的大鼠的微粒体可以被包含纯化的细胞色素P-448、NADPH-细胞色素还原酶和辅助因子的重组系统所取代。BP-7，8-二醇和BPDE的反应中间体与GSH或半胱氨酸的偶联反应不需要微粒或半胱氨酸的存在，因此表明这是一个非催化反应。这些结果强调了GSH和半胱氨酸等细胞亲核试剂在活性苯并(A)芘(BP)中间体失活中的重要性，也为最终致癌物BPDE进一步活化为更多的活性去亲核剂提供了证据，因此可能与BP诱导的致癌调控有关。
Trans-7, 8-dihydroxy-7, 8-dihydrobenzo(a)pyrene (BP-7, 8-diol) and the anti-isomer oftrans-7, 8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) were found to be activated by microsomes isolated from 3-methylcholanthrene (MC)-treated rats to reactive intermediates that bound covalently to microsomal proteins. The extent of binding was markedly reduced by the presence of reduced glutathione (GSH) or cysteine. Fluorescence spectroscopic studies on the products derived from BP-7,8-diol and BPDE after microsomal activation in presence of GSH or cysteine revealed the formation of a common reactive intermediate with unique fluorescence properties. The involvement of cytochrome P-448 in the activation of BP-7,8-diol and BPDE to protein-binding products was inferred by the requirement for NADPH and almost complete inhibition by α-naphtho-flavone. Furthermore, microsomes from MC-treated rats could be replaced by a reconstituted system containing purified cytochrome P-448, NADPH-cytochrome reductase and co-factors. The conjugation of the reactive intermediates from BP-7,8-diol and BPDE with GSH or cysteine did not require the presence of either microsomes or cyutosol, thus indicating a non-catalytic reaction. These results emphasize the importance of cellular nucleophiles such as GSH and cysteine in the deactivation of reactive benzo(a)pyrene (BP) intermediates and also provides evidence for the further activation of the ultimate carcinogen BPDE to more reactive dectro-philes and may thus have relevance concerning the regulation of BP-induced carcinogenesis.