The effect of dose and enzyme inducers on the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats.
Male Fischer 344 rats were given a single dose of 0.03-30 mg/kg of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), the radioactivity in urine and feces was determined over 48 h, and the major metabolites were identified and quantified. Dose had little effect on the profile of metabolites in the urine but did influence the profile in the feces. PhIP was more efficiently metabolized at higher doses. In addition, rats were pretreated with Aroclor 1254 (PCB), 3-methylcholanthrene (MC), phenobarbital (PB), PhIP and corn oil prior to a single dose of [14C]PhIP, and compared with a control group receiving [14C]PhIP only. The major metabolites in the urine and feces were quantitated for each group, as well as PhIP binding to serum proteins, hemoglobin and selected tissues. Pretreatment with MC and PCB resulted in an increase in the amount of 4'-hydroxylation of PhIP and a decrease in the amount of N-hydroxylated metabolites in the urine. Pretreatment with PB resulted in an increase in the amount of N-hydroxylated metabolites, but a decrease in 4'-hydroxylation. Pretreatment with either MC or PCB resulted in an increase in PhIP binding to the liver and kidney, while reducing the binding in other tissues. Animals pretreated with PhIP showed few significant differences from the untreated group, while pretreatment with PB in general resulted in a decrease of PhIP binding in tissues.
Watkins
B E
BE
Biochemistry Division, National Cancer Center Research Institute, Tokyo, Japan.
Suzuki
M
M
Wallin
H
H
Wakabayashi
K
K
Alexander
J
J
Vanderlaan
M
M
Sugimura
T
T
Esumi
H
H
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005243:Feces / Q000737:chemistry; D007093:Imidazoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D009153:Mutagens / Q000378:metabolism* / Q000493:pharmacokinetics; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D001140:Aroclors; D007093:Imidazoles; D009153:Mutagens; D020111:Chlorodiphenyl (54% Chlorine); D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital