Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.
Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.
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DOI：
10.1073/pnas.73.8.2594
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发表时间：
1976-08
影响因子：
11.1
通讯作者：
S. K. Yang;D. Mccourt;P. Roller;H. Gelboin
中科院分区：
文献类型：
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作者：
S. K. Yang;D. Mccourt;P. Roller;H. Gelboin
苯并(A)芘被大鼠肝微粒体的混合功能氧化酶和环氧化物水合酶(乙二醇水解酶(环氧化物形成)，EC 4.2.1.63)代谢并立体定向转化为单一对映体(-)r-7，t-8-二羟基-7，8-二氢苯(A)芘。这种对映体进一步被混合功能的氧化酶立体选择性地代谢成主要是二醇环氧化物，r-7，t-8-dihydroxy-t-9，10-oxy-7，8，9，10-tetrahydrobenzol(a)pyrene，其中7-羟基和9，10-环氧化物是反式的。其他未知代谢物也是由r-7，t-8-二羟基-7，8-二氢苯并(A)芘形成的。外消旋r-7，t-8-二羟基-7，8-二氢苯并(A)-芘被代谢转化为r-7，t-8-dihydroxy-t-9，10-oxy-7，8，9，10-tetrahydrobenzo(a)pyrene和r-7，t-8-dihydroxy-c-9，10-oxy-7，8，9，10-tetrahydrobenzo(a)pyrene.二醇环氧化合物在水介质中不稳定，通过高压液相色谱、质谱分析和紫外吸收光谱分析，确定其为r-7，t-8-dihydroxy-t-9，10-oxy-7，8，9，10-tetrahydrobenzo(a)pyrene和r-7，t-8-dihydroxy-c-9，10-oxy-7，8，9，10-tetrahydrobenzo(a)pyrene，其四羟基四氢苯并(A)芘的水解产物与真实合成化合物的迁移率相同。在NADPH存在下，二元醇-环氧化物也被还原成不同的三羟基并五氢苯并(A)芘。由于人工合成的外消旋r-7，t-8-dihydroxy-t-9，10-oxy-7，8，9，10-tetrahydrobenzo(a)pyrene在哺乳动物细胞中具有很强的诱变性，我们认为它是代谢形成的二醇环氧化物，可能是苯并(A)芘的最终致癌形式。
Benzo(a)pyrene is metabolically and stereospecifically converted by mixed-function oxidases of rat liver microsomes and epoxide hydratase (glycol hydro-lyase (epoxide-forming), EC 4.2.1.63)to the single enantiomer (-)r-7,t-8-dihydroxy-7,8-dihydrobenzol (A) pyrene. This enantiomer is further metabolized stereoselectively by the mixed-function oxidases to predominantly the diol-epoxide, r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzol(a)pyrene in which the 7-hydroxyl and the 9,10-epoxide are trans. Other unidentified metabolites are also formed from the r-7,t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene. Racemic r-7,t-8-dihydroxy-7,8-dihydrobenzo(a)-pyrene is converted metabolically to both r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. The diol-epoxides are unstable in aqueous medium, and their identification and characterization as r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene were accomplished by the identity of their tetrahydroxytetrahydrobenzo(a)pyrenes hydrolysis products with those of the authentic synthetic compounds with respect to mobility on high-pressure liquid chromatography and mass and ultraviolet absorption spectral analysis. The diol-epoxides were also reduced in the presence of NADPH to distinct trihydroxypentahydrobenzo(a)pyrenes. Since the synthetic racemic r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene is very highly mutagenic in mammalian cells, we suggest that it is the metabolically formed diol-epoxide that may be an ultimate carcinogenic form of benzo(a)pyrene.