The effect of enzyme induction on the stereoselective metabolism of optically pure (-)1R,2R- and (+)1S,2S-dihydroxy-1,2-dihydrobenz-[a]anthracenes to vicinal 1,2-dihydrodiol 3,4-epoxides by rat liver microsomes.
The effect of enzyme induction on the stereoselective metabolism of optically pure (-)1R,2R- and (+)1S,2S-dihydroxy-1,2-dihydrobenz-[a]anthracenes to vicinal 1,2-dihydrodiol 3,4-epoxides by rat liver microsomes.
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酶诱导对光学纯 (-)1R,2R- 和 ( )1S,2S-二羟基-1,2-二氢苯并-[a]蒽立体选择性代谢为邻位 1,2-二氢二醇 3,4-环氧化物的影响
DOI：
10.1093/carcin/4.5.629
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发表时间：
1983
期刊：
影响因子：
4.7
通讯作者：
S. K. Yang
中科院分区：
文献类型：
--
作者：
M. Chou;P. Chiu;P. Fu;S. K. Yang
采用正相高效液相色谱法对其非对映异构体二（-）薄荷乙酸酯进行拆分，然后进行碱催化水解，得到光学纯净的（-）和（+）反式-1,2-二羟基-1,2-二氢苯[a]蒽（BA反式-1,2-二氢二醇）。用激子手性法测定了(-)- ba反式-1,2-二氢生物具有1R，2R绝对立体化学性质。每个对映体和外消旋BA反式-1,2-二氢二醇与未处理的，苯巴比妥(PB)-和3-甲基胆蒽（MC）处理的雄性Sprague-Dawley大鼠的肝微粒体孵育。BA反式-1,2-二氢二醇的外消旋体和对映体分别由BA反式-1,2-二氢二醇反3,4-环氧化合物（3,4-环氧氧反式到1-羟基）和syn-3,4-环氧化合物（3,4-环氧氧顺式到1-羟基）水解而成，分别生成两个1,2,3,4-四羟基-1,2,3,4-四氢苯[a]蒽（BA 1,2,3,4-四氢苯）。所有的英国航空公司1、2、3,4-tetrols被确定通过对比反相h.p.l.c.保留时间tetrols及其附近的醋酸酯的水解产品化学合成英航trans-1, 2-dihydrodiol anti-3, 4-epoxide,英航trans-1, 2-dihydrodiol syn-3, 4-epoxide,英航trans-3, 4-dihydrobiol anti-1, 2-epoxide,和BA trans-3 4-dihydrodiol syn-1, 2-epoxide,分别通过附近的丙酮化合物层形成的模式,和紫外吸收和大规模光谱分析。从(-)-BA反式-1,2-二氢二醇代谢来看，mc处理大鼠肝微粒体生成的主要产物是BA反式-1,2-二氢二醇抗3,4-环氧化物，而未处理和pb处理大鼠肝微粒体生成的主要产物是BA反式-1,2-二氢二醇syn-3,4-环氧化物。相反，BA反式-1,2-二氢二醇syn-3,4-环氧化物是三种大鼠肝微粒体制剂(+)-BA反式-1,2-二氢二醇代谢的主要产物。经pb处理的大鼠肝微粒体催化外消旋体和对映体BA反式-1,2-二氢二醇代谢的速率高于未处理和mc处理的大鼠肝微粒体。所有BA 1,2,3,4-四醇代谢物均具有旋光活性。结果表明，“湾区”BA反式-1,2-二氢二醇主要在邻近的3,4-双键上被大鼠肝微粒体代谢，每个对映体BA反式-1,2-二氢二醇被代谢成一对非对映体BA反式-1,2-二氢二醇3,4-环氧化物，其立体选择性程度取决于大鼠肝微粒体中细胞色素P-450的组成形式。
The optically pure (-) and (+)trans-1,2-dihydroxy-1,2-dihydrobenz[a]anthracenes (BA trans-1,2-dihydrodiol) were obtained through the resolution of their diastereomeric di(-)menthoxyacetates by normal-phase h.p.l.c., followed with base-catalyzed hydrolysis. The (-)-BA trans-1,2-dihydrobiol has been determined to have 1R,2R absolute stereochemistry by exciton chirality method. Each of the enantiomeric and racemic BA trans-1,2-dihydrodiol was incubated with liver microsomes from untreated, phenobarbital (PB)-, and 3-methylcholanthrene (MC)-treated male Sprague-Dawley rats. The racemic and enantiomeric BA trans-1,2-dihydrodiols were each metabolized to two 1,2,3,4-tetrahydroxy-1,2,3,4-tetrahydrobenz[a]anthracenes (BA 1,2,3,4-tetrol) derived from the hydrolysis of BA trans-1,2-dihydrodiol anti-3,4-epoxide (the 3,4-epoxy oxygen is trans to the 1-hydroxyl group) and syn-3,4-epoxide (the 3,4-epoxy oxygen is cis to the 1-hydroxyl group), respectively. All the BA 1,2,3,4-tetrols were identified by comparing the reversed-phase h.p.l.c. retention times of tetrols and their vicinal acetonides with the hydrolysis products of the chemically synthesized BA trans-1,2-dihydrodiol anti-3,4-epoxide, BA trans-1,2-dihydrodiol syn-3,4-epoxide, BA trans-3,4-dihydrobiol anti-1,2-epoxide, and BA trans-3,4-dihydrodiol syn-1,2-epoxide, respectively, by their modes of forming vicinal acetonides, and by ultraviolet absorption and mass spectral analyses. From the metabolism of (-)-BA trans-1,2-dihydrodiol, a BA trans-1,2-dihydrodiol anti-3,4-epoxide was the major product formed by liver microsomes from MC-treated rats whereas a BA trans-1,2-dihydrodiol syn-3,4-epoxide was the major product formed by liver microsomes from either untreated or PB-treated rats. In contrast, BA trans-1,2-dihydrodiol syn-3,4-epoxide was the major product formed from the metabolism of (+)-BA trans-1,2-dihydrodiol by all three rat liver microsomal preparations. Liver microsomes from PB-treated rats were found to catalyze the metabolism of both the racemic and the enantiomeric BA trans-1,2-dihydrodiols at a rate higher than those by liver microsomes from untreated and MC-treated rats. All BA 1,2,3,4-tetrol metabolites were found to be optically active by circular dichroism spectral analysis. The results indicate that the 'bay-region' BA trans-1,2-dihydrodiol is metabolized by rat liver microsomes predominantly at the vicinal 3,4-double bond and that each enantiomeric BA trans-1,2-dihydrodiol is metabolized to a pair of diastereomeric BA trans-1,2-dihydrodiol 3,4-epoxides with varying degrees of stereoselectivity depending on the constitutive forms of cytochrome P-450 in the rat liver microsomal preparations.