Penning T M
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
Chem Biol Interact. 1993 Oct;89(1):1-34. doi: 10.1016/0009-2797(93)03203-7.
Dihydrodiol dehydrogenase(s) (DD) have been implicated in the detoxication of proximate (trans-dihydrodiol) and ultimate carcinogenic (anti-diol-epoxide) metabolites of polycyclic aromatic hydrocarbons (PAHs). These activities are catalyzed by soluble hydroxysteroid dehydrogenases and/or by aldehyde reductases. Molecular cloning indicates tha these enzymes have a high degree of sequence identity with members of the aldo-keto reductase super family. Substrate specificity studies indicate that non-K-region trans-dihydrodiols are the preferred substrates and that anti-dio-epoxides are not oxidized by the enzyme. The products of the DD reaction are transient catechols which auto-oxidize to PAH-o-quinones. As a consequence of this auto-oxidation superoxide anion, hydrogen peroxide and semiquinone radicals are generated. Studies on the biotransformation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene indicate that in subcellular fractions from uninduced rat liver, DD plays a significant role in the metabolism of this proximate carcinogen. Thus, the formation of benzo[a]pyrene-7,8-dione is only superseded by the formation of tetraols which are derived from the anti-diol epoxide of benzo[a]pyrene [anti-BPDE;(+/-)-anti-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene]. PAH-o-quinones produced by DD can inactivate the enzyme. These PAH-o-quinones also vary in their reactivity towards cellular nucleophiles, their cytotoxicity and their genotoxicity. Non-bay region and methylated bay-region PAH-o-quinones generated by DD are the most reactive Michael acceptors, and are also the most cytotoxic in hepatoma cells. Cytotoxicity results from the 1e- redox-cycling of the PAH-o-quinone, concomittant production of superoxide anion and a subsequent alteration in redoxstate. PAH-o-quinones are also genotoxic thus [3H]-benzo[a]pyrene-7,8-dione readily forms deoxyguanosine-adducts with native calf-thymus DNA, i.e., to the same extent as anti-BPDE. The cytotoxic and genotoxic properties of PAH-o-quinones suggest that DD may initiate a hitherto unrecognized pathway of PAH activation.
二氢二醇脱氢酶（DD）与多环芳烃（PAHs）的近端（反式二氢二醇）和最终致癌（反式二氢二醇环氧化物）代谢产物的解毒作用有关。这些活性由可溶性羟类固醇脱氢酶和/或醛还原酶催化。分子克隆表明，这些酶与醛酮还原酶超家族成员具有高度的序列同一性。底物特异性研究表明，非K区域反式二氢二醇是首选底物，而反式二氢二醇环氧化物不会被该酶氧化。DD反应的产物是瞬时儿茶酚，其会自动氧化为PAH - o - 醌。由于这种自动氧化，会产生超氧阴离子、过氧化氢和半醌自由基。对（±） - 反式 - 7,8 - 二羟基 - 7,8 - 二氢苯并[a]芘的生物转化研究表明，在未诱导的大鼠肝脏亚细胞组分中，DD在这种近端致癌物的代谢中起重要作用。因此，苯并[a]芘 - 7,8 - 二酮的形成仅被源自苯并[a]芘反式二氢二醇环氧化物[反式 - BPDE；（±） - 反式 - 7β，8α - 二羟基 - 9α，10α - 环氧 - 7,8,9,10 - 四氢苯并[a]芘]的四醇的形成所取代。DD产生的PAH - o - 醌可以使该酶失活。这些PAH - o - 醌对细胞亲核试剂的反应性、细胞毒性和遗传毒性也各不相同。DD产生的非湾区和甲基化湾区PAH - o - 醌是最具反应性的迈克尔受体，在肝癌细胞中也是最具细胞毒性的。细胞毒性源于PAH - o - 醌的单电子氧化还原循环、超氧阴离子的伴随产生以及随后氧化还原状态的改变。PAH - o - 醌也具有遗传毒性，因此[³H] - 苯并[a]芘 - 7,8 - 二酮很容易与天然小牛胸腺DNA形成脱氧鸟苷加合物，即与反式 - BPDE的程度相同。PAH - o - 醌的细胞毒性和遗传毒性表明，DD可能启动了一条迄今未被认识的PAH活化途径。
