DIHYDRODIOL DEHYDROGENASE AND ITS ROLE IN POLYCYCLIC AROMATIC HYDROCARBON METABOLISM

被引:71
作者
PENNING, TM
机构
[1] Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia
关键词
DIHYDRODIOL DEHYDROGENASE; POLYCYCLIC AROMATIC HYDROCARBONS; OMICRON-QUINONES; CYTOTOXICITY; GENOTOXICITY;
D O I
10.1016/0009-2797(93)03203-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 that 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-diol-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-dihydro-benzo[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 Thus, the formation of benzo[a]pyrene-7,8-dione is only superseded by the formation of tetraols which are derived from the anti-diol epoxide of benzo[a]pyrene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-7beta,8alpha-dihydroxy-9alpha,10alpha-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 le- redox-cycling of the PAH-o-quinone, concomittant production of superoxide anion and a subsequent alteration in redox-state. PAH-o-quinones are also genotoxic thus [H-3]-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.
引用
收藏
页码:1 / 34
页数:34
相关论文
共 80 条
[41]   MUTAGENICITY OF ISOMERIC DIOL-EPOXIDES OF BENZO [ALPHA] PYRENE AND BENZ [ALPHA] ANTHRACENE IN S-TYPHIMURIUM TA98 AND TA100 AND IN V79 CHINESE-HAMSTER CELLS [J].
MALAVEILLE, C ;
KUROKI, T ;
SIMS, P ;
GROVER, PL ;
BARTSCH, H .
MUTATION RESEARCH, 1977, 44 (03) :313-325
[42]  
MCMILLENJACKSON AL, 1990, P AM ASS CANCER RES, V31
[43]  
MELIKIAN AA, 1982, CANCER RES, V42, P1239
[44]   POLYCYCLIC AROMATIC HYDROCARBON (PAH) ORTHO-QUINONE CONJUGATE CHEMISTRY - KINETICS OF THIOL ADDITION TO PAH ORTHO-QUINONES AND STRUCTURES OF THIOETHER ADDUCTS OF NAPHTHALENE-1,2-DIONE [J].
MURTY, VS ;
PENNING, TM .
CHEMICO-BIOLOGICAL INTERACTIONS, 1992, 84 (02) :169-188
[45]   CHARACTERIZATION OF MERCAPTURIC ACID AND GLUTATHIONYL CONJUGATES OF BENZO[A]PYRENE-7,8-DIONE BY 2-DIMENSIONAL NMR [J].
MURTY, VS ;
PENNING, TM .
BIOCONJUGATE CHEMISTRY, 1992, 3 (03) :218-224
[46]  
NAGAO M, 1978, MUTAGENESIS MICROBIO, V1, P99
[47]  
NAKAGAWA M, 1989, CHEM PHARM BULL, V37, P2852
[48]   EXCEPTIONAL MUTAGENICITY OF A BENZO[ALPHA]PYRENE DIOL EPOXIDE IN CULTURED MAMMALIAN-CELLS [J].
NEWBOLD, RF ;
BROOKES, P .
NATURE, 1976, 261 (5555) :52-54
[49]  
NORDQVIST M, 1981, MOL PHARMACOL, V19, P168
[50]  
NUTTER LM, 1991, J BIOL CHEM, V266, P16380