Characterization of hepatic microsomal cytochrome P-450 from rats treated with methylsulphonyl metabolites of polychlorinated biphenyl congeners.
The inducing potency of 3-methylsulphonyl(MeSO2)-2,2',4',5,5'-pentachlorobiphenyl (pentaCB), which was one of the major MeSO2 metabolites of polychlorinated biphenyls (PCBs) present in seal blubber, on the hepatic drug metabolizing enzyme activities was examined in comparison with that of the parent compound and phenobarbital (PB). The inducing fashion of the above enzymes and changes in the contents of PB-inducible P-450 forms by 2,3',4',5-tetrachlorobiphenyl (tetraCB) (IU-70), 2,2',3',4',5-pentaCB (IU-87), 2,2',4',5,5'-pentaCB (IU-101) and 2,2',3',4',5,5'-hexachlorobiphenyl (hexaCB) (IU-141), and their MeSO2 metabolites were investigated in rats. Administration at various doses (0.2-1.0 mumol/kg) of 3-MeSO2-2,2',4',5,5'-pentaCB produced nearly dose-related increases in the hepatic concentration of this methyl sulphone, in the contents of cytochromes P-450 and b5, and in activities of aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and benzo[a]pyrene hydroxylase of liver microsomes. Major PB-inducible forms, CYP2B1, CYP2B2, CYP3A2 and CYP2C6 were induced with four PCBs (342 mumol/kg) and their 3-MeSO2 metabolites (0.5-10 mumol/kg), indicating that 3-MeSO2 metabolites were strong PB-type inducers of hepatic drug-metabolizing enzymes. 3-MeSO2-2,2',4',5,5'-pentaCB was an especially strong inducer. On the other hand, four PB-inducible forms of cytochrome P-450 were not induced with the 4-MeSO2 isomers. The relation between liver concentrations of the corresponding 3-MeSO2 derivatives and induction of four PB-inducible forms of cytochrome P-450 after administration of four PCBs and their 3-MeSO2 derivatives further confirmed that the 3-MeSO2 metabolites played an important role in the induction which parent PCB congeners caused on the hepatic drug-metabolizing enzyme system.
Kato
Y
Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Haraguchi
K
K
Kawashima
M
M
Yamada
S
S
Isogai
M
M
Masuda
Y
Y
Kimura
R
R
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000378:metabolism / Q000633:toxicity*; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism*
D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C089877:Cyp2c6v1 protein, rat; D000072467:Cytochrome P450 Family 2; C025619:steroid 16-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D013255:Steroid 21-Hydroxylase; D010634:Phenobarbital