Induction of hepatic microsomal drug-metabolizing enzymes by methylsulphonyl metabolites of polychlorinated biphenyl congeners in rats.
The effect of methylsulphonyl (MeSO2) metabolites of 2,3',4',5-tetrachlorobiphenyl (tetraCB) (IU-70), 2,2',3',4',5-pentachlorobiphenyl (pentaCB) (IU-87), 2,2',4',5,5'-pentaCB (IU-101) and 2,2',3',4',5,5'-hexachlorobiphenyl (hexaCB) (IU-141), on the hepatic microsomal drug-metabolizing enzyme system was investigated in rats. The administration of 3-MeSO2-2,3',4',5-tetraCB (10 mumol/kg), 3-MeSO2-2,2',3',4',5-pentaCB (0.5 mumol/kg), 3-MeSO2-2,2',4',5,5'-pentaCB (0.5 mumol/kg) and 3-MeSO2-2,2',3',4',5,5'-hexaCB (2 mumol/kg) to rats significantly increased the contents of cytochromes P-450 and b5 and the activities of aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and benzo[a]pyrene hydroxylase. From these results, it is suggested that the 3-MeSO2 derivatives studied are possibly potent phenobarbital-like inducers of microsomal drug-metabolizing enzymes. On the other hand, 4-MeSO2-2,3',4',5-tetraCB, 4-MeSO2-2,2',3',4',5-pentaCB, 4-MeSO2-2,2',4',5,5'-pentaCB and 4-MeSO2-2,2',3',4',5,5'-hexaCB had almost no effect on both cytochrome contents and these enzyme activities. After 96 h, following administration of 2,3',4',5-tetraCB, 2,2',3',4',5-pentaCB, 2,2',4',5,5'-pentaCB and 2,2',3',4',5,5'-hexaCB (342 mumol/kg each), significant increases in contents of these two cytochromes and in activities of these enzymes were observed. The relationship between liver concentrations of 3-MeSO2-PCBs after administration of four PCB congeners and that after administration of their 3-MeSO2 derivatives, and increases in the contents of both cytochromes and activities of drug-metabolizing enzyme suggests that the 3-MeSO2 metabolites derived from PCBs studied play an important role in the induction of the drug-metabolizing enzymes by the parent PCB congeners.
Kato
Y
Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Haraguchi
K
K
Kawashima
M
M
Yamada
S
S
Masuda
Y
Y
Kimura
R
R
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004781:Environmental Exposure; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*; D014018:Tissue Distribution
D013450:Sulfones; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D015660:7-Alkoxycoumarin O-Dealkylase; D001579:Benzopyrene Hydroxylase; D000633:Aminopyrine N-Demethylase