Leblond Francois A, Petrucci Martin, Dubé Pierre, Bernier Gilbert, Bonnardeaux Alain, Pichette Vincent
Nephrology Service and Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Faculty of Medicine, Université de Montréal, Québec, Canada.
J Am Soc Nephrol. 2002 Jun;13(6):1579-85. doi: 10.1097/01.asn.0000017575.50319.77.
Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P < 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P < 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (>40%, P < 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P < 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. N-Demethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P < 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.
慢性肾衰竭（CRF）与肠道药物代谢降低有关。其机制仍知之甚少，但有一种假说认为与细胞色素P450水平降低有关。本研究旨在探讨CRF对肠道细胞色素P450的影响。定义了两组大鼠，即CRF大鼠（通过5/6肾切除术诱导）和对照配对喂养大鼠。评估了肠道微粒体中细胞色素P450的总水平、细胞色素P450同工酶的蛋白质和mRNA表达，以及红霉素的体外N-去甲基化（CYP3A活性探针）和7-乙氧基异吩恶唑酮O-脱乙基酶活性（CYP1A探针）。两组大鼠体重相似。与对照配对喂养动物相比，CRF大鼠的肌酐清除率降低了77%（P<0.001）。CRF大鼠的肠道细胞色素P450总活性降低了32%（P<0.001）。CRF大鼠中CYP1A1和CYP3A2蛋白表达显著降低（>40%，P<0.001）。两组中CYP2B1、CYP2C6和CYP2C11水平相同。RT-PCR分析显示CRF大鼠中CYP1A1和CYP3A2基因表达明显下调（P<0.001）。虽然CRF中肠道细胞色素P450水平降低，但地塞米松仍可诱导其表达。与对照大鼠相比，CRF大鼠中红霉素的N-去甲基化和7-乙氧基异吩恶唑酮O-脱乙基酶活性降低了25%（P<0.05）。总之，大鼠中的CRF与基因表达降低继发的肠道细胞色素P450活性（主要是CYP1A1和CYP3A2）降低有关。
