EFFECTS OF MOLECULAR SUBSTITUTION PATTERNS ON THE CYTOCHROME-P-450-DEPENDENT METABOLISM OF 2,2',3,5,5',6-HEXACHLOROBIPHENYL AND 2,2',3,4,4',6-HEXACHLOROBIPHENYL BY RAT-LIVER MICROSOMAL MONOOXYGENASES

被引:20
作者
BORLAKOGLU, JT
DREW, MGB
WILKINS, JPG
DILS, RR
机构
[1] UNIV READING, DEPT BIOCHEM & PHYSIOL, READING RG6 2AH, BERKS, ENGLAND
[2] UNIV READING, DEPT CHEM, READING RG6 2AH, BERKS, ENGLAND
[3] MAFF, HARPENDEN LAB, HARPENDEN, ENGLAND
关键词
MOLECULAR SUBSTITUTION; POLYCHLORINATED BIPHENYL (PCB); CYTOCHROME-P-450; MONOOXYGENASE;
D O I
10.1016/0304-4165(90)90030-Z
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
The metabolism by rat hepatic microsomal cytochrome P-450-dependent monooxygenases of several model substrates that are specific for individual isoforms of cytochrome P-450 and the metabolism by these monooxygenases of two structurally related isomers of hexachlorobiphenyl was studied. The most striking result was that 2,2',3,5,5',6-hexachlorobiphenyl was metabolised in vitro at the rate of 4.5 pmol/mg microsomal protein per min, whereas the other isomer 2,2',3,4,4',6-hexachlorobiphenyl was not metabolised at detectable rates. This finding provides strong evidence for a regioselective oxidative attack by cytochrome P-450-dependent monooxygenase with preferential insertion of oxygen at meta-para unsubstituted carbon atoms. Investigations into the mechanism of this oxidative attack suggest that the ortho hydrogen atom at carbon atom C-6' of 2,2',3,4,4',6-hexachlorobiphenyl was associated with a lower charge (0.075 e) compared with the meta or para hydrogen atoms at carbon atom C-3' and C-4' of 2,2',3,5,5',6-hexachlorobiphenyl (0.086 e). In addition, measurement of the main C-C bond length using MOPAC calculations and X-ray crystalographic data suggests significant differences in the bond-length distance, with the main bond lengths of 1.390, 1.385 and 1.374-angstrom, respectively, for bridgehead to ortho (C1-C2), for ortho to meta (C2-C3), and for meta to para bonds. These results provide evidence that the preferential meta-para oxidative attack is linked to a shorter carbon-carbon bond length and a more positive charge distribution of the corresponding hydrogen atoms.
引用
收藏
页码:167 / 175
页数:9
相关论文
共 36 条
[1]   CAMBRIDGE CRYSTALLOGRAPHIC DATA CENTER - COMPUTER-BASED SEARCH, RETRIEVAL, ANALYSIS AND DISPLAY OF INFORMATION [J].
ALLEN, FH ;
BELLARD, S ;
BRICE, MD ;
CARTWRIGHT, BA ;
DOUBLEDAY, A ;
HIGGS, H ;
HUMMELINK, T ;
HUMMELINKPETERS, BG ;
KENNARD, O ;
MOTHERWELL, WDS ;
RODGERS, JR ;
WATSON, DG .
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1979, 35 (OCT) :2331-2339
[2]   EVIDENCE FOR THE INDUCTION OF CYTOCHROME P-452 IN RAT-LIVER BY AROCLOR-1254, A COMMERCIAL MIXTURE OF POLYCHLORINATED-BIPHENYLS [J].
BORLAKOGLU, JT ;
EDWARDSWEBB, JD ;
DILS, RR ;
WILKINS, JPG ;
ROBERTSON, LW .
FEBS LETTERS, 1989, 247 (02) :327-329
[3]   POLYCHLORINATED-BIPHENYLS IN FISH-EATING SEA BIRDS - MOLECULAR-FEATURES AND METABOLIC INTERPRETATIONS [J].
BORLAKOGLU, JT ;
WILKINS, JPG ;
WALKER, CH .
MARINE ENVIRONMENTAL RESEARCH, 1988, 24 (1-4) :15-19
[4]   COMPARATIVE ASPECTS OF CONGENER SPECIFIC PCB METABOLISM [J].
BORLAKOGLU, JT ;
WALKER, CH .
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1989, 14 (02) :127-131
[5]  
BORLAKOGLU JT, 1989, THESIS U READING UK
[6]   VORONOI BINDING-SITE MODELS - CALCULATION OF BINDING MODES AND INFLUENCE OF DRUG-BINDING DATA ACCURACY [J].
BOULU, LG ;
CRIPPEN, GM .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1989, 10 (05) :673-682
[7]   SYSTEMATIC EFFECTS OF CRYSTAL-PACKING FORCES - BIPHENYL FRAGMENTS WITH H-ATOMS IN ALL 4 ORTHO POSITIONS [J].
BROCK, CP ;
MINTON, RP .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1989, 111 (13) :4586-4593
[8]   ETHOXYPHENOXAZONES, PENTOXYPHENOXAZONES, AND BENZYLOXYPHENOXAZONES AND HOMOLOGS - A SERIES OF SUBSTRATES TO DISTINGUISH BETWEEN DIFFERENT INDUCED CYTOCHROMES-P-450 [J].
BURKE, MD ;
THOMPSON, S ;
ELCOMBE, CR ;
HALPERT, J ;
HAAPARANTA, T ;
MAYER, RT .
BIOCHEMICAL PHARMACOLOGY, 1985, 34 (18) :3337-3345
[9]  
BURKE MD, 1975, DRUG METAB DISPOS, V3, P245
[10]  
CADOGAN JIG, 1962, J CHEM SOC, P4257