Induction of peroxisomal enzymes by a tetrazole-substituted 2-quinolinylmethoxy leukotriene D4 antagonist.
The induction of hepatic peroxisomal beta-oxidation and the peroxisomal bifunctional enzyme (PBE) by the tetrazole-substituted leukotriene D4 receptor antagonist RG 7152 was evaluated in vivo following subchronic treatment in the mouse, rat, guinea pig, dog, and rhesus monkey. The ability of RG 7152 to induce this enzyme system in rat extrahepatic tissues reported to respond to peroxisome proliferators and in vitro in primary rat hepatocytes was also investigated. Western blot analysis for PBE and beta-oxidation assays revealed significant induction by RG 7152 in liver homogenates from rats and mice with a lesser effect in guinea pigs and monkeys and no effect in dogs. The degree of induction in rat liver was less than that observed in a positive control group treated with clofibrate (CF). There was slight induction of PBE in rat kidney and small intestine by CF, whereas RG 7152 elicited a minimal response in the kidney and no effect in the small intestine. In vitro, RG 7152 produced a response that was greater than that produced by diethylhexyl phthalate, approximately equivalent to that produced by clofibric acid, but less than that produced by bezafibrate. Dose-response comparison of RG 7152 with the tetrazole-substituted leukotriene D4 antagonist LY 171883 to be slightly more potent than RG 7152. Thus, RG 7152 represents a second chemical class of tetrazole-substituted leukotriene D4 antagonist that causes peroxisomal enzyme induction in rodents.
Kelley
M
M
Drug Safety Division, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426.
Groth-Watson
A
A
Knoble
D
D
Kornbrust
D
D
D000818:Animals; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D006168:Guinea Pigs; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology*; D010088:Oxidoreductases / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*
D011804:Quinolines; D013777:Tetrazoles; C063535:RG 7152; D017998:Leukotriene D4; D010088:Oxidoreductases; D002994:Clofibrate; D010634:Phenobarbital