Metabolism in vitro of 3,4,3',4'- and 2,5,2',5'-tetrachlorobiphenyl by rat liver microsomes and highly purified cytochrome P-450.
Metabolism of two polychlorinated biphenyls, 3,4,3',4'- and 2,5,2',5'-tetrachlorobiphenyl (TCB), was studied using rat liver microsomes and the four forms of cytochrome P-450 (P-450), P-450b, P-450e, P-450c and P-450d. At first, effects of various inducers of P-450 such as phenobarbital (PB), 3-methylcholanthrene (MC), isosafrole (ISF) and pregnenolone 16 alpha-carbonitrile on the formation of metabolites of these TCBs by liver microsomes were compared. 3,4,3',4'-TCB was significantly metabolized by liver microsomes from MC-treated rats to form two previously reported metabolites, 4-hydroxy-3,5,3',4'-TCB and 5-hydroxy-3,4,3',4'-TCB with a relative ratio of 2.5:1. Incubation with microsomes from untreated or PB-treated rats produced none of the metabolites. On the other hand, 2,5,2',5'-TCB was metabolized to 3-hydroxy-2,5,2',5'-TCB most easily by liver microsomes from PB-treated rats and at a moderate rate by liver microsomes from ISF-treated rats. Activities of microsomes from untreated or MC-treated rats to hydroxylate 2,5,2',5'-TCB were low or undetectable. When these TCB hydroxylase activities were examined with a reconstituted system consisting of each P-450, reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase, dilauroylphosphatidylcholine and NADPH-generating system, only P-450c catalyzed both the 4- and 5-hydroxylations of 3,4,3',4'-TCB at a ratio of 2.2:1. On the contrary, the hydroxylation of 2,5,2',5'-TCB proceeded efficiently with P-450b and P-450e, being more efficient with the former. P-450d did not show any catalytic activity toward 3,4,3',4'-TCB and 2,5,2',5'-TCB.(ABSTRACT TRUNCATED AT 250 WORDS)
Ishida
C
C
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Koga
N
N
Hanioka
N
N
Saeki
H K
HK
Yoshimura
H
H
D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012451:Safrole / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D013438:Sulfhydryl Compounds; C009407:2,5,2',5'-tetrachlorobiphenyl; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D006899:Mixed Function Oxygenases; D010424:Pentobarbital; D012451:Safrole; C015959:isosafrole; C028451:3,4,3',4'-tetrachlorobiphenyl