Deutsch J, Leutz J C, Yang S K, Gelboin H V, Chiang Y L, Vatsis K P, Coon M J
Proc Natl Acad Sci U S A. 1978 Jul;75(7):3123-7. doi: 10.1073/pnas.75.7.3123.
Highly purified cytochromes P-450(LM2) and P-450(LM4) and partially purified P-450(LM1), P-450(LM3b), and P-450(LM7) from rabbit liver microsomes exhibit different catalytic activities in the metabolism of benzo[a]pyrene (BzP) and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)trans-7,8-diol] in a reconstituted enzyme system. The two highly purified cytochromes also exhibit differences in the activation of BzP and (-)trans-7,8-diol to intermediates that bind to DNA, as well as in the stereoselective conversion of (-)trans-7,8-diol to the highly mutagenic and carcinogenic diol-epoxides r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (diol-epoxide I) and r - 7,t - 8 - dihydroxy - c - 9,10 - oxy - 7,8,9,10 - tetrahydrobenzo[a]pyrene (diol-epoxide II). P-450(LM2) is more active than P-450(LM4) in the metabolism of BzP and in its conversion to products that bind to DNA. In contrast, P-450(LM4) is more active than P-450(LM2) in the metabolism of (-)trans-7,8-diol and in its conversion to products that bind to DNA. The ratio of activity (percent substrate metabolized) with BzP relative to that with (-)trans-7,8-diol is 21 for P-450(LM2) and 0.3 for P-450(LM4); P-450(LM1), P-450(LM3b), and P-450(LM7) gave intermediate ratios. Marked stereoselectivity in the oxygenation of the (-)trans-7,8-diol to the highly mutagenic and putatively carcinogenic diol-epoxides I and II was observed with P-450(LM4), whereas the other preparations showed less selectivity. The ratio of diolepoxide I to diol-epoxide II ranges from 0.3 for P-450(LM7) to 11 for P-450(LM4). The substrate specificity and regio- and stereo-selectivity of the different forms of cytochrome P-450 may regulate the balance between activation and detoxification pathways of BzP and therefore determine the susceptibility of individual tissues, strains, and species to the carcinogenic action of BzP.
从兔肝微粒体中高度纯化的细胞色素P - 450（LM2）和P - 450（LM4）以及部分纯化的P - 450（LM1）、P - 450（LM3b）和P - 450（LM7）在重组酶系统中对苯并[a]芘（BzP）和（-）-反式-7,8 - 二羟基-7,8 - 二氢苯并[a]芘[（-）反式-7,8 - 二醇]的代谢表现出不同的催化活性。这两种高度纯化的细胞色素在将BzP和（-）反式-7,8 - 二醇激活为与DNA结合的中间体方面，以及在将（-）反式-7,8 - 二醇立体选择性转化为高致突变性和致癌性的二醇环氧化物r - 7,t - 8 - 二羟基 - t - 9,10 - 氧代-7,8,9,10 - 四氢苯并[a]芘（二醇环氧化物I）和r - 7,t - 8 - 二羟基 - c - 9,10 - 氧代-7,8,9,10 - 四氢苯并[a]芘（二醇环氧化物II）方面也存在差异。P - 450（LM2）在BzP的代谢及其转化为与DNA结合的产物方面比P - 450（LM4）更具活性。相反，P - 450（LM4）在（-）反式-7,8 - 二醇的代谢及其转化为与DNA结合的产物方面比P - 450（LM2）更具活性。P - 450（LM2）对BzP的活性（代谢底物的百分比）与对（-）反式-7,8 - 二醇的活性之比为21，而P - 450（LM4）为0.3；P - 450（LM1）、P - 450（LM3b）和P - 450（LM7）给出的比值介于两者之间。观察到P - 450（LM4）在将（-）反式-7,8 - 二醇氧化为高致突变性和可能致癌的二醇环氧化物I和II方面具有明显的立体选择性，而其他制剂的选择性较低。二醇环氧化物I与二醇环氧化物II的比值范围从P - 450（LM7）的0.3到P - 450（LM4）的11。细胞色素P - 450不同形式的底物特异性、区域选择性和立体选择性可能调节BzP激活和解毒途径之间的平衡，因此决定个体组织、品系和物种对BzP致癌作用 的易感性。
