COMPARATIVE BIOCHEMICAL AND MORPHOMETRIC CHANGES ASSOCIATED WITH INDUCTION OF THE HEPATIC MIXED-FUNCTION OXIDASE SYSTEM IN THE RAT

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)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-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 dosage. LTB4 omega-, but not omega-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 dose-dependent increase in ECOD activity was observed but there was no change in LTB4 omega- or omega-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, LTB4-omega-hydroxylase activity was increased by the 18 and 60 mg/kg/day dosages of SK&F 86002; LTB4 omega-1 hydroxylase was unchanged. Quantitative evaluation of hepatocyte ultrastructural characteristics indicated that the volume percent (Vv) of smooth endoplasmic reticulum (SER) was increased but that 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 mitochondrial 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. Mitochondrial Vv was unaffected. These studies confirm that SK&F 86002 is an inducer of the cytochrome P-450 mixed function oxidase system but with an induction profile somewhat different from phenobarbital. The principal difference being that SK&F 86002 was a Potent inducer of LTB4 omega-hydroxylase, a feature not associated with phenobarbital induction. SK&F 86002 and phenobarbital share similar ultrastructural hepatic changes both increasing the Vv of hepatocyte SER. However, a reduction in the Vv of mitochondria within the hepatocyte was only associated with phenobarbital treatment; this occurred on both days 3 and 14. These observations suggest that both biochemical and morphological differences are present in hepatocytes from rats treated with differing P-450 inducers.