Chou M W, Chiu P L, Fu P P, Yang S K
Carcinogenesis. 1983;4(5):629-38. doi: 10.1093/carcin/4.5.629.
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.
通过正相高效液相色谱法拆分其非对映体二（-）薄荷氧基乙酸酯，然后进行碱催化水解，得到了光学纯的（-）和（+）反式-1,2-二羟基-1,2-二氢苯并[a]蒽（BA反式-1,2-二氢二醇）。通过激子手性法确定（-）-BA反式-1,2-二氢二醇具有1R,2R绝对立体化学结构。将对映体和外消旋体的BA反式-1,2-二氢二醇分别与未处理的、经苯巴比妥（PB）和3-甲基胆蒽（MC）处理的雄性Sprague-Dawley大鼠的肝微粒体一起温育。外消旋体和对映体的BA反式-1,2-二氢二醇分别代谢为两种1,2,3,4-四羟基-1,2,3,4-四氢苯并[a]蒽（BA 1,2,3,4-四醇），它们分别由BA反式-1,2-二氢二醇反式-3,4-环氧化物（3,4-环氧氧与1-羟基处于反式）和顺式-3,4-环氧化物（3,4-环氧氧与1-羟基处于顺式）水解产生。通过比较四醇及其邻位丙酮化物的反相高效液相色谱保留时间与化学合成的BA反式-1,2-二氢二醇反式-3,4-环氧化物、BA反式-1,2-二氢二醇顺式-3,4-环氧化物、BA反式-3,4-二氢二醇反式-1,2-环氧化物和BA反式-3,4-二氢二醇顺式-1,2-环氧化物的水解产物的保留时间，以及它们形成邻位丙酮化物的方式、紫外吸收和质谱分析，鉴定了所有的BA 1,2,3,4-四醇。在（-）-BA反式-1,2-二氢二醇的代谢过程中，MC处理大鼠的肝微粒体形成的主要产物是BA反式-1,2-二氢二醇反式-3,4-环氧化物，而未处理或PB处理大鼠的肝微粒体形成的主要产物是BA反式-1,2-二氢二醇顺式-3,4-环氧化物。相反，在所有三种大鼠肝微粒体制剂中，（+）-BA反式-1,2-二氢二醇代谢形成的主要产物是BA反式-1,2-二氢二醇顺式-3,4-环氧化物。发现PB处理大鼠的肝微粒体催化外消旋体和对映体BA反式-1,2-二氢二醇的代谢速率高于未处理和MC处理大鼠的肝微粒体。通过圆二色光谱分析发现，所有BA 1,2,3,4-四醇代谢物均具有光学活性。结果表明，“湾区”BA反式-1,2-二氢二醇主要在大鼠肝微粒体的邻位3,4-双键处代谢，并且每种对映体的BA反式-1,2-二氢二醇根据大鼠肝微粒体制剂中细胞色素P-450的组成形式以不同程度的立体选择性代谢为一对非对映体的BA反式-1,2-二氢二醇3,4-环氧化物。
