Induction of cytochrome P450 3A (CYP 3A) by E 5110, a non-steroidal anti-inflammatory agent (NSAID), and typical CYP 3A inducers in primary cultures of dog hepatocytes.
First, the effect of E 5110, a non-steroidal anti-inflammatory agent (NSAID), on cytochrome P450 subfamilies in dog hepatocyte culture was examined. E 5110 has been shown to cause a drug interaction in dogs and humans via induction of cytochrome P450 3A (CYP 3A). When dog hepatocytes were cultured for 72 h in the presence of 2-30 microM E 5110, the activity levels of ethoxycoumarin O-deethylase (ECOD) and testosterone 6 beta-hydroxylase (6 beta-OH-T) rose dose-dependently. Subsequent Western blot analysis of microsomes from hepatocyte cultures indicated the presence of higher amounts of CYP 2B and 3A proteins than those of the control. Next, the P450 inducing potency of E 5110 was compared with those of phenobarbital, rifampicin, phenytoin and carbamazepine, which induce CYP 3A in human subjects and human hepatocyte cultures. E 5110 was found to be nearly as effective as phenytoin, but less potent than rifampicin, on the basis of 6 beta-OH-T induction.
Nishibe
Y
Y
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Hirata
M
M
D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004285:Dogs; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009853:Omeprazole / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011760:Pyrrolidinones; C054091:E 5110; D002220:Carbamazepine; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D015660:7-Alkoxycoumarin O-Dealkylase; D019392:Cytochrome P-450 CYP2E1; C022657:steroid hormone 6-beta-hydroxylase; D003022:Clotrimazole; D002994:Clofibrate; D009853:Omeprazole; D012293:Rifampin; D010634:Phenobarbital