Induction and inhibition of cytochrome P450 and drug-metabolizing enzymes by climbazole.
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'-phosphate (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.
Kobayashi
Yasuna
Y
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Suzuki
Michiya
M
Ohshiro
Naomi
N
Sunagawa
Takashi
T
Sasaki
Tadanori
T
Oguro
Takiko
T
Tokuyama
Shogo
S
Yamamoto
Toshinori
T
Yoshida
Takemi
T
D000818:Animals; D015152:Blotting, Northern; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C108286:climbazole; D006899:Mixed Function Oxygenases