Puccinelli Emanuela, Gervasi Pier Giovanni, La Marca Margherita, Beffy Pascale, Longo Vincenzo
Istituto di Fisiologia Clinica, CNR, Pisa, Italy.
Xenobiotica. 2010 Aug;40(8):525-35. doi: 10.3109/00498254.2010.489125.
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.
在本研究中，我们在对照猪和经苯巴比妥（PB）处理的猪的肝脏、肾脏、小肠、呼吸道及嗅鼻黏膜中，从活性和/或转录水平研究了CYP2C33、CYP2C42、CYP2C49、CYP2B22、CYP3A22、CYP3A29和CYP3A46的表达及诱导性。PB处理导致肝脏中所有分析的细胞色素P450（CYPs）的mRNA水平上调，肾脏中CYP2C42和CYP2C49的mRNA水平上调，小肠中CYP2C42、CYP2C49、CYP2B22和CYP3A的mRNA水平上调。在经PB处理的猪的肝脏微粒体中，这些转录激活伴随着人CYP2B6、CYP3A、CYP2C9、CYP2C19各种标志物活性的增加。在肝外组织中，仅在肾脏中观察到PB对CYP2C9标志物活性有显著诱导作用。综上所述，我们的结果表明，在猪中给予PB至少在肝脏中除了诱导CYP2B22和CYP3A外，还在转录和活性水平诱导了CYP2C33、CYP2C42和CYP2C49的表达。此外，我们的研究结果表明，猪CYP2C的催化活性在所观察到的活性以及与人类对应物的活性方面存在差异。因此，在以药物作为CYP2C的底物和/或诱导剂的研究中，将猪用作人类模型时应谨慎考虑。
