CHARACTERIZATION OF THE EFFECTS OF TEBUFELONE ON HEPATIC CYTOCHROMES P450 IN THE BEAGLE DOG

Tebufelone -dimethylethyl)-4-hydroxy-phenyl]-hex-5-yne-1-one) is an in vestigational ditertiary butylphenol nonsteroidal anti-inflammatory dr ug. The purpose of the present study was to assess the effects of tebu felone on hepatocyte ultrastructure and hepatic cytochromes P450 (P450 s) in the beagle dog after 2 weeks of oral administration at dose leve ls of 0, 5, 15, 50, and inn mg/kg/day (N = 1/sex/dose level), Hepatic tissue was obtained at necropsy for histologic, ultrastructural, and b iochemical evaluation, Hepatocellular hypertrophy was observed in only a single tebufelone-treated dog (50 mg/kg). Electron microscopic eval uation, however, revealed marked dose-dependent increases in smooth en doplasmic reticulum in all of the tebufelone treatment groups, Biochem ical indicators suggested that tebufelone produced mixed effects on he patic P450s. p-Nitroanisole O-demethylase and, to a greater extent, et hoxyresorufin O-deethylase activities were decreased with increasing t ebufelone dose. The precise mechanism by which tebufelone decreased et hoxyresorufin O-deethylase activity in dogs is unknown, but it was not by competitive inhibition, P450 inactivation, or reduced CYP1A expres sion, Tebufelone treatment increased NADPH-dependent cytochrome c redu ctase, total P450, and indicators of CYP2B11 (chloramphenicol covalent binding and immunochemically determined 2B11) and CYP3A12 (erythromyc in N-demethylase, triacetyloleandomycin spectral complex formation, te stosterone 6 beta-hydroxylase, and immunochemically determined 3A12), The largest increase in the 2B11 and 3A12 markers occurred in the 50 o r 100 mg/kg treatment groups, The greatest increase in CYP2B11 markers produced by tebufelone treatment ranged from 2- to 3-fold, whereas th e increase in CYP3A12 markers ranged from 5- to 10-fold, The changes i n hepatic ultrastructure and increases in CYP2B11 and CYP3A12 markers produced by tebufelone in dogs are similar to that reported for phenob arbital.