Mechanism-based inactivation of hepatic cytochrome P450 2C6 and P450 3A1 following in vivo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine to rats: differences from previously observed in vitro results.
Using progesterone 21-hydroxylase as a selective substrate for P450 2C6 in phenobarbital-treated male rats, and androstenedione and progesterone 6 beta-hydroxylases as well as erythromycin N-demethylase as selective markers for P450 3A1 in dexamethasone-treated female rats, we have shown that these P450 isozymes undergo mechanism-based inactivation after in vivo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC). These results differ from our previous studies where no inactivation was observed after in vitro administration of 4-ethyl DDC to rat hepatic microsomes. We show that the differences between the in vivo and in vitro effects of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) analogues are due to the presence of residual 4-ethyl DDC in the in vitro experiments causing time-independent competitive inhibition and obscuring observation of mechanism-based inactivation.
Kimmett
S M
SM
Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada.
McNamee
J P
JP
Marks
G S
GS
D000818:Animals; D002855:Chromatography, Thin Layer; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072467:Cytochrome P450 Family 2; D003907:Dexamethasone / Q000494:pharmacology; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013255:Steroid 21-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*
D065607:Cytochrome P-450 Enzyme Inhibitors; C030826:3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine; D003997:Dicarbethoxydihydrocollidine; D003907:Dexamethasone; D013250:Steroid Hydroxylases; C089877:Cyp2c6v1 protein, rat; D000072467:Cytochrome P450 Family 2; C022657:steroid hormone 6-beta-hydroxylase; D013255:Steroid 21-Hydroxylase; D010634:Phenobarbital