Induction of hepatic and extrahepatic cytochrome P-450 and monooxygenase activities by N-substituted imidazoles.
1. Seven N-substituted imidazoles, with abilities to induce rat hepatic cytochrome P-450 from 1.5- to 4-fold after 3 days of treatment (75 mg/kg daily), were investigated for their concurrent inductive effect in kidney, intestine and lung. 2. The ability of a compound to induce cytochrome P-450 in the liver did not correlate with the ability to induce in extrahepatic tissues, the highest magnitude hepatic inducer (clotrimazole) having little inductive effect in other organs. 3. Induction of cytochrome P-450 concentration was greater in kidney and intestine than in lung but, with the exception of the two imidazoles bearing either a benzyl or a 2-naphthylmethyl substituent, the degree of induction in the extrahepatic organs did not approach that seen in liver. 4. Different monooxygenase activities were preferentially induced by the individual N-substituted imidazoles in a single tissue, and activities induced by a compound in one tissue were not uniformly induced by that compound in other tissues. Induction of activities did not always correlate with an increase in cytochrome P-450 concentration.
Harmsworth
W L
WL
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112.
Franklin
M R
MR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010105:Oxygenases / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D015262:Xenobiotics / Q000378:metabolism
D007093:Imidazoles; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases