Michaud Josée, Naud Judith, Chouinard Jérôme, Désy François, Leblond Francois A, Desbiens Karine, Bonnardeaux Alain, Pichette Vincent
Service de néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec, Canada.
J Am Soc Nephrol. 2006 Nov;17(11):3041-8. doi: 10.1681/ASN.2006010035. Epub 2006 Oct 4.
Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10(-9) M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.
慢性肾衰竭（CRF）与肝脏细胞色素P450（P450）减少所继发的药物代谢降低有关。解释这种降低的主要理论是尿毒症患者血液中存在某些因素。本研究检验了甲状旁腺激素（PTH）可能就是这种因素的假说。本研究的目的是确定：（1）PTH在大鼠尿毒症血清诱导的肝细胞P450下调中的作用；（2）PTH在CRF大鼠肝脏P450下调中的作用；（3）PTH对肝细胞中P450的影响。为此，（1）将肝细胞与用抗PTH抗体去除PTH的CRF大鼠血清或与CRF甲状旁腺切除（CRF-PTX）大鼠的血清一起孵育；（2）评估PTX对CRF大鼠肝脏P450的影响；（3）确定PTH对肝细胞中P450的影响。从CRF血清中去除PTH完全逆转了CRF血清对肝细胞中P450的下调作用。向去除PTH的CRF血清中添加PTH（10⁻⁹ M）可诱导P450降低，类似于未去除PTH的CRF血清。与CRF血清相比，CRF-PTX大鼠的血清对肝细胞中的P450没有影响。向CRF-PTX血清中添加PTH可诱导P450出现与CRF血清相似的降低。最后，PTX可防止CRF大鼠肝脏P450的降低。总之，PTH是CRF大鼠肝脏P450下调的主要介导因素。
