ABSTRA(=T This study characterized the induction of the rat hepatic cytochrome P-450-dependent mixed function oxidase system by SK&F 86002 [6-(4'-~uorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-(2,l-b)thiazole], 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-0-deethylase (ECOD) and leukotriene B,(LTB,) w-and w-1 hydroxylase were measured. Ultrastmctural 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. LTB, wand w-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 dosage. LTB, w-, but not w-1 hydroxylase activity was increased by both the 18 and 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, A dosedependent increase in ECOD activity was observed but there was no change in LTB, w-or 0-1 hydroxylase activity on day 14.Administration of SK&F 86002 (60 mg/kg/day) for 14 days increased the liver to body weight ratio. Microsomal protein content was unaffected but cytochrome P-450 content and ECOD activity were increased at the 60 mg/kg/day dosage. Similar to the day 3 observation, LTB, w-hydroxylase activity was increased by the 18 and 60 mg/kg/day dosages of SK&F 86002; LTB, w-1 hydroxylase was unchanged.Quantitative evaluation of hepatocyte ultrastructural characteristics indicated that the volume percent (Vv) of smooth endoplasmic reticulum (SER) was increased.hut;fQat cytosol and mitochondrial Vv significantly decreased after 3 days of phenobarbital treatment. Three days-of treatment'with SK&F 86002 also increased the Vv of SER; Vv of cytosol was decreased but the mitochondria1 Vv was unchanged from control values.SER Vv was increased after 14 days of phenobarbital treatment but cytosol Vv was not significantly affected. Similar to the 3 day results, mitochondrial Vv decreased in phenobarbital treated rats. SK&F 86002 treatment for 14 days increased the SER Vv and decreased cytosol Vv. Mitochondria1 Vv was unaffected.These studies...
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