Characterization of the effects of tebufelone on hepatic cytochromes P450 in the beagle dog.
Tebufelone (1-[3,5-bis(1,1-dimethylethyl)-4-hydroxy-phenyl]-hex-5-yne-1-one) is an investigational ditertiary butylphenol nonsteroidal anti-inflammatory drug. The purpose of the present study was to assess the effects of tebufelone on hepatocyte ultrastructure and hepatic cytochromes p450 (P450s) in the beagle dog after 2 weeks of oral administration at dose levels of 0, 5, 15, 50, and 100 mg/kg/day (N = 1/sex/dose level). Hepatic tissue was obtained at necropsy for histologic, ultrastructural, and biochemical evaluation. Hepatocellular hypertrophy was observed in only a single tebufelone-treated dog (50 mg/kg). Electron microscopic evaluation, however, revealed marked dose-dependent increases in smooth endoplasmic reticulum in all of the tebufelone treatment groups. Biochemical indicators suggested that tebufelone produced mixed effects on hepatic P450s. p-Nitroanisole O-demethylase and, to a greater extent, ethoxyresorufin O-deethylase activities were decreased with increasing tebufelone dose. The precise mechanism by which tebufelone decreased ethoxyresorufin O-deethylase activity in dogs in unknown, but it was not by competitive inhibition, P450 inactivation, or reduced CYP1A expression. Tebufelone treatment increased NADPH-dependent cytochrome c reductase, total P450, and indicators of CYP2B11 (chloramphenicol covalent binding and immunochemically determined 2B11) and CYP3A12 (erythromycin N-demethylase, triacetyloleandomycin spectral complex formation, testosterone 6 beta-hydroxylase, and immunochemically determined 3A12). The largest increase in the 2B11 and 3A12 markers occurred in the 50 or 100 mg/kg treatment groups. The greatest increase in CYP2B11 markers produced by tebufelone treatment ranged from 2- to 3-fold, whereas the increase in CYP3A12 markers ranged from 5- to 10-fold. The changes in hepatic ultrastructure and increases in CYP2B11 and CYP3A12 markers produced by tebufelone in dogs are similar to that reported for phenobarbital.
Smith
B J
BJ
Procter & Gamble Pharmaceuticals, Inc., Drug Safety Assessment Department, Miami Valley Laboratories, Cincinnati, OH 45253-8707, USA.
Zupan
L A
LA
Hu
J K
JK
Diters
R W
RW
Gibson
G W
GW
Norton
J N
JN
D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D002701:Chloramphenicol / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004285:Dogs; D004790:Enzyme Induction; D005260:Female; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating / Q000096:biosynthesis / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000378:metabolism; D014217:Troleandomycin / Q000378:metabolism
D000480:Alkynes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065607:Cytochrome P-450 Enzyme Inhibitors; D010636:Phenols; D002701:Chloramphenicol; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; C026048:4-nitroanisole O-demethylase; D010090:Oxidoreductases, O-Demethylating; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C090278:cytochrome P-450 CYP2B11 (dog); C475779:cytochrome P-450 CYP3A12 (canine); C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D009245:NADH Dehydrogenase; C064268:tebufelone