Hepatic peroxisomal and drug metabolizing activity in CD-1 mice after oral treatment with a novel 5-lipoxygenase inhibitor.
The effects of zileuton, a 5-lipoxygenase inhibitor, on hepatic peroxisomal enzyme activity as well as hepatic drug metabolizing activity in male and female CD-1 mice were assessed after oral administration of the drug (50, 150, or 450 mg/kg/day) for 14 days. The effects were compared to those in mice receiving clofibrate (CLOF;462 mg/kg/day, po) or sodium phenobarbital (PB; 50 mg/kg/day, po). Zileuton pretreatment caused hepatomegaly and elevated liver peroxisomal KCN-insensitive palmitoyl CoA oxidase activity in a dose-dependent manner. However, these changes were marginal (< or = 121% increase), when compared to those elicited by CLOF (approximately 370% increase). In both sexes, zileuton pretreatment also caused a dose-dependent increase in the levels of liver microsomal cytochrome P450 2B and cytochrome P450 4A (CYP4A) proteins, and their associated monoxygenase activity. In the case of CYP4A, the induction of lauric acid 12-hydroxylase activity by zileuton was more pronounced in female (maximal 851% increase) than in male mice (maximal 111% increase). Based on the dose normalized response observed in CD-1 mice, zileuton can be considered a relatively weak inducer of peroxisome enzyme activities (cf.CLOF) and a moderate inducer of cytochromes P450. Moreover, zileuton exhibits characteristics of both a PB- and a CLOF-type hepatic enzyme inducer, especially in the female mice.
Rodrigues
A D
AD
Drug Metabolism Department, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Machinist
J M
JM
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006529:Hepatomegaly / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000633:toxicity; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects
D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System; C063449:zileuton; D006918:Hydroxyurea