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

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)

• Authors: M O Howard, L W Schwartz, J F Newton, C W Qualls Jr, L A Yodis, J R Ventre
• Journal: Toxicologic pathology (Toxicol Pathol) Vol. 19 Issue 2 Pg. 115-22 ( 1991) ISSN: 0192-6233 [Print] United States
• PMID: 1663268 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Imidazoles
• Thiazoles
• Leukotriene B4
• Cytochrome P-450 Enzyme System
• 6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole
• Mixed Function Oxygenases
• 7-Alkoxycoumarin O-Dealkylase
• Cytochrome P-450 CYP4A
• Phenobarbital

Topics

• 7-Alkoxycoumarin O-Dealkylase (analysis)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Body Weight (drug effects)
• Cytochrome P-450 CYP4A
• Cytochrome P-450 Enzyme System (analysis, metabolism, physiology)
• Dose-Response Relationship, Drug
• Enzyme Induction (drug effects)
• Hypertrophy (chemically induced, pathology)
• Imidazoles (pharmacology)
• Leukotriene B4 (analysis)
• Liver (enzymology, physiology, ultrastructure)
• Male
• Microscopy, Electron
• Mixed Function Oxygenases (analysis, metabolism, physiology)
• Organ Size (drug effects)
• Organelles (ultrastructure)
• Phenobarbital (pharmacology)
• Rats
• Rats, Inbred Strains
• Thiazoles (pharmacology)