Marnett L J, Reddy A, Pruess-Schwartz D, Ji C
A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Princess Takamatsu Symp. 1990;21:63-73.
Dihydrodiolepoxides (BPDE) are reactive derivatives that appear to mediate the genotoxic effects of benzo[a]pyrene (BP) and several other polycyclic hydrocarbons. Their formation requires sequential epoxidation, hydration, and epoxidation steps. The first epoxidation step is catalyzed by cytochrome P-450 isoenzymes whereas the second is catalyzed by cytochromes P-450 and assorted species of oxygen radicals (in particular peroxyl radicals). The stereochemistry of epoxidation of the procarcinogen 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) is a useful tool with which to dissect the contributions of cytochrome P-450-dependent and independent pathways. [32P]-Postlabeling techniques were developed to analyze the diastereomeric composition of BPDE-deoxynucleoside-bis-phosphate adducts recovered from DNA of target tissues for BP tumorigenesis. Application of these techniques revealed that cytochrome P-450 is the major contributor to BPDE production in mouse skin in vivo. Following administration of BP or (+)-BP-7,8-diol to female CD-1 mice, only minor amounts of adducts derived from peroxyl radical epoxidation were detected. In contrast, pretreatment of the animals with the tumor promoter tetradecanoyl phorbol acetate (TPA) led to the formation of sizeable amounts of non-cytochrome P-450-dependent adducts following coincident administration of (+)-BP-7,8-diol with a second dose of TPA. The results demonstrate that although oxygen radicals appear to play a minor role in tumor initiation by BP, they may play a major role in tumor promotion by phorbol esters.
二氢二环氧苯并芘（BPDE）是具有反应活性的衍生物，似乎介导了苯并[a]芘（BP）及其他几种多环烃的遗传毒性作用。其形成需要依次经过环氧化、水化和环氧化步骤。第一步环氧化由细胞色素P - 450同工酶催化，而第二步由细胞色素P - 450和各种氧自由基（特别是过氧自由基）催化。前致癌物7,8 - 二羟基 - 7,8 - 二氢苯并[a]芘（BP - 7,8 - 二醇）的环氧化立体化学是剖析细胞色素P - 450依赖性和非依赖性途径贡献的有用工具。[32P] - 后标记技术被开发用于分析从BP肿瘤发生的靶组织DNA中回收的BPDE - 脱氧核苷 - 双磷酸加合物的非对映体组成。这些技术的应用表明，细胞色素P - 450是体内小鼠皮肤中BPDE产生的主要贡献者。给雌性CD - 1小鼠施用BP或（+） - BP - 7,8 - 二醇后，仅检测到少量源自过氧自由基环氧化的加合物。相反，用肿瘤促进剂十四烷酰佛波醇乙酸酯（TPA）预处理动物，在（+） - BP - 7,8 - 二醇与第二剂TPA同时施用后，导致形成大量非细胞色素P - 450依赖性加合物。结果表明，尽管氧自由基在BP引发肿瘤中似乎起次要作用，但它们可能在佛波酯促进肿瘤方面起主要作用。
