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Comparative biochemical and morphometric changes associated with induction of the hepatic mixed function oxidase system in the rat.

M O Howard·L W Schwartz·J F Newton·C W Qualls·L A Yodis·J R Ventre
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Abstract

This study characterized the induction of the rat hepatic cytochrome P-450-dependent mixed function oxidase system by SK&F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-(2,1-b)thia zole], an inhibitor of both the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The induction characteristics of SK&F 86002 were compared to those of the classical inducer, phenobarbital, and morphological features of both SK&F 86002 and phenobarbital induced hepatocellular hypertrophy were quantitated. Rats were administered either SK&F 86002 (6, 18, or 60 mg/kg/day, po) or phenobarbital (8, 24, 80 mg/kg/day, ip) for 3 or 14 consecutive days. Liver to body weight ratio, total hepatic microsomal protein and cytochrome P-450 content, ethoxycoumarin-O-deethylase (ECOD) and leukotriene B4(LTB4) omega- and omega-1 hydroxylase were measured. Ultrastructural morphometry of the liver from control, and high dose SK&F 86002 (60 mg/kg/day) and phenobarbital (80 mg/kg/day) treated rats was completed. On day 3, phenobarbital increased liver to body weight ratio but only at the 80 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity increased in a dose-dependent fashion. LTB4 omega- and omega-1 hydroxylase activities were unaffected. Administration of SK&F 86002 for 3 days increased the liver to body weight ratio at both the 18 and 60 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity was significantly increased by the 60 mg/kg/day dosages of SK&F 86002. On day 14, phenobarbital increased the liver to body weight ratio and microsomal protein content but again only at the 80 mg/kg/day dosage. Cytochrome P-450 content was increased by all dosages.(ABSTRACT TRUNCATED AT 250 WORDS)

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7-Alkoxycoumarin O-DealkylaseAnimalsAnti-Inflammatory Agents, Non-SteroidalBody WeightCytochrome P-450 CYP4ACytochrome P-450 Enzyme SystemDose-Response Relationship, DrugEnzyme InductionHypertrophyImidazolesLeukotriene B4LiverMaleMicroscopy, ElectronMixed Function OxygenasesOrgan SizeOrganellesPhenobarbitalRatsRats, Inbred StrainsThiazolesComparative StudyJournal Article

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M O Howard, L W Schwartz, J F Newton, C W Qualls, L A Yodis, J R Ventre. 1991. Comparative biochemical and morphometric changes associated with induction of the hepatic mixed function oxidase system in the rat.. https://doi.org/10.1177/019262339101900205

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