Guenthner T M, Oesch F
Cancer Lett. 1981 Jan;11(3):175-83. doi: 10.1016/0304-3835(81)90105-1.
The effects of modulation of microsomal epoxide hydrolase activity on the binding of calf thymus DNA of benzo[alpha]pyrene metabolically activated by rat liver microsomes were investigated. In systems where microsomal epoxide hydrolase levels were not manipulated, 2 major bound species, one derived from 9-hydroxybenzo[alpha]pyrene and the other derived from benzo[alpha]pyrene 7,8-dihydrodiol, were found in approximately equivalent amounts. When epoxide hydrolase levels were increased, either by addition in vitro of purified enzyme or by induction in vivo by trans-stilbene oxide, the binding of the benzo[alpha]pyrene 7,8-dihydrodiol product was increased, while the binding of the 9-hydroxybenzo[alpha]pyrene product was practically eliminated. When microsomal epoxide hydrolase activity was decreased by selective inhibition with low concentrations of 1,1,1-trichloropropene 2,3-oxide, the binding of the species derived from 9-hydroxybenzo[alpha]pyrene was increased several-fold, while that of the species derived from benzo[alpha]pyrene 7,8-dihydrodiol was greatly decreased. The results indicate that the binding species derived from 9-hydroxybenzo[alpha]pyrene is formed through a metabolic pathway leading to an epoxide which is a substrate of microsomal epoxide hydrolase and that microsomal epoxide hydrolase is important in regulating the pattern of binding of individual microsomally-formed benzo[alpha]pyrene metabolites to DNA.
研究了微粒体环氧化物水解酶活性的调节对大鼠肝微粒体代谢活化的苯并[a]芘与小牛胸腺DNA结合的影响。在未控制微粒体环氧化物水解酶水平的系统中，发现了两种主要的结合产物，一种来自9-羟基苯并[a]芘，另一种来自苯并[a]芘7,8-二氢二醇，二者含量大致相当。当通过体外添加纯化酶或通过反式氧化苯乙烯在体内诱导来提高环氧化物水解酶水平时，苯并[a]芘7,8-二氢二醇产物的结合增加，而9-羟基苯并[a]芘产物的结合几乎被消除。当用低浓度的1,1,1-三氯丙烯2,3-氧化物进行选择性抑制使微粒体环氧化物水解酶活性降低时，来自9-羟基苯并[a]芘的结合产物增加了几倍，而来自苯并[a]芘7,8-二氢二醇的结合产物则大大减少。结果表明，9-羟基苯并[a]芘衍生的结合产物是通过一条导致环氧化物的代谢途径形成的，该环氧化物是微粒体环氧化物水解酶的底物，并且微粒体环氧化物水解酶在调节单个微粒体形成的苯并[a]芘代谢产物与DNA的结合模式中起重要作用。
