The 3-methylcholanthrene-mimetic effect of 4,4'-dichlorobiphenyl-treatment on phenacetin-induced hepatic glutathione depletion and liver microsomal phenacetin O-deethylation in rats.
Both 4,4'-dichlorobiphenyl (4,4'-DCB) and 3-methylcholanthrene (3-MC) caused a substantial increase of phenacetin-induced hepatic glutathione (GSH) depletion, whereas phenobarbital (PB) had no effect, suggesting that 4,4'-DCB possesses cytochrome P-448 inducing activity. The O-deethylation of phenacetin by liver microsomes from control and PB- and 4,4'-DCB-treated rats showed biphasic Michaelis-Menten kinetics, in contrast to the monophasic course after pretreatment with 3-MC. Hepatic phenacetin levels indicated that in vivo interaction with only a high affinity site is involved in the O-deethylation of phenacetin. 4,4'-DCB and 3-MC caused marked increases in intrinsic clearance and extraction ratio of phenacetin, whereas control values were obtained after PB-treatment. Because of an absence of a spectral change at low phenacetin concentrations, it could not be demonstrated whether the observed differences in metabolism should be ascribed to a change in binding of phenacetin to cytochrome P-450. The results of this study indicate that after pretreatment with various enzyme inducers the phenacetin-induced hepatic GSH depletion strongly correlates with microsomal phenacetin O-deethylation. Further, these findings suggest a discrepancy between 4,4'-DCB and PB in cytochrome P-450 inducing activity, as 4,4'-DCB mimics 3-MC in the induction of phenacetin O-deethylase. The difference between 4,4'-DCB and PB is discussed in relation to the multiplicity and induction of cytochrome P-450 isoenzymes.
D000082:Acetaminophen / Q000378:metabolism; D000818:Animals; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D010088:Oxidoreductases / Q000378:metabolism; D010615:Phenacetin / Q000378:metabolism* / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000082:Acetaminophen; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C029861:4,4'-dichlorobiphenyl; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D010615:Phenacetin; D005978:Glutathione; D010634:Phenobarbital