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)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)
Howard
M O
MO
Department of Experimental Pathology, SmithKline Beecham Pharmaceuticals, Swedeland, Pennsylvania 19479.
Schwartz
L W
LW
Newton
J F
JF
Qualls
C W
CW
Yodis
L A
LA
Ventre
J R
JR
D015660:7-Alkoxycoumarin O-Dealkylase / Q000032:analysis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000032:analysis; D008099:Liver / Q000201:enzymology* / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D015388:Organelles / Q000648:ultrastructure; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D013844:Thiazoles; D007975:Leukotriene B4; D003577:Cytochrome P-450 Enzyme System; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D006899:Mixed Function Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D042926:Cytochrome P-450 CYP4A; D010634:Phenobarbital