Biol. Pharm. Bull., 25(1),53-57, January 2002

Regular Articles

Induction and Inhibition of Cytochrome P450 and Drug-Metabolizing Enzymes by Climbazole

Yasuna KOBAYASHI,^a Michiya SUZUKI,^c Naomi OHSHIRO,^b Takashi SUNAGAWA,^b Tadanori SASAKI,^b Takiko OGURO,^b Shogo TOKUYAMA,^a Toshinori YAMAMOTO,^a and Takemi YOSHIDA^{* ,c}

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University,^a 1–5–8 Hatanodai, Shinagawa-ku, Tokyo 142–8555, Japan, Department of Physiology and Biophysics, University of Texas Medical Branch at Galveston,^b Galveston, Texas 77555–1031, U.S.A., and Department of Biochemical Toxicology, School of Pharmaceutical Sciences,Showa University,^c 1–5–8 Hatanodai, Shinagawa-ku, Tokyo 142–8555, Japan.

To determine the effect of climbazole on hepatic microsomal cytochrome P450 (P450) and drug-metabolizing enzymes, four different P450 isoforms (CYP2B1, 3A2, 2E1, and 2C12) were examined in female Long–Evans rats. Treatment of rats with climbazole resulted in the induction of P450 content. Climbazole both induced and inhibited aminopyrine N-demethylase activity, but not erythromycin N-demethylase activity. Uridine 5'-phos-phate (UDP)-glucuronosyl transferase and glutathione S-transferase activities were also increased with climbazole treatment. Immunoblot analyses revealed that climbazole induces CYP2B1 and CYP3A2 at the lower dose examined, but it failed to increase CYP2B1 at the higher dose. Northern blot analysis revealed that climbazole markedly increases P450 2B1 mRNA. These results indicate that climbazole induces and inhibits P450-dependent drug-metabolizing enzymes in vivo and may have the dose-differential effect on CYP2B1 in rat liver.

Key words cytochrome P450; climbazole; enzyme induction; imidazole