Expression and inducibility by phenobarbital of CYP2C33, CYP2C42, CYP2C49, CYP2B22, and CYP3As in porcine liver, kidney, small intestine, and nasal tissues.
In this study, the expression and inducibility of CYP2C33, CYP2C42, CYP2C49, CYP2B22, CYP3A22, CYP3A29, and CYP3A46 were investigated at activity and/or transcriptional level in liver, kidney, small intestine, respiratory, and olfactory nasal mucosa of control and phenobarbital (PB)-treated pigs. PB treatment resulted in an up-regulation of mRNA levels of all analyzed CYPs in liver, of CYP2C42 and CYP2C49 in kidney, of CYP2C42, CYP2C49, CYP2B22, and CYP3As in small intestine. In liver microsomes from PB-treated pigs, these transcriptional activations were accompanied by an increase of various marker activities of human CYP2B6, CYP3As, CYP2C9, CYP2C19. Among the extrahepatic tissues, a significant induction by PB was observed only in kidney for the marker activities of CYP2C9. Taken together, our results demonstrated that the PB administration in pigs induced at least in liver, in addition to CYP2B22 and CYP3As, the expression of CYP2C33, CYP2C42, and CYP2C49 at transcriptional and activity levels. Furthermore our findings showed that the catalytic activities of porcine CYP2Cs are different amongst those observed and with respect to the human counterparts. Thus, the use of pigs as a model for humans in studies using drugs as substrates and/or inducers of CYP2Cs should be considered carefully.
Istituto di Fisiologia Clinica, CNR, Pisa, Italy.
Emanuela
E
Puccinelli
Pier Giovanni
PG
Gervasi
Margherita
M
La Marca
Pascale
P
Beffy
Vincenzo
V
Longo
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D007421:Intestine, Small / Q000201:enzymology*; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D009297:Nasal Mucosa / Q000201:enzymology / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation
D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D010634:Phenobarbital