Lee Young-Mi, Song Im-Sook, Kim Sang Geon, Lee Myung Gull, Chung Suk-Jae, Shim Chang-Koo
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Shinlim 9-dong, Kwanak-gu, Seoul 151-742, Korea.
J Pharm Sci. 2003 Jul;92(7):1323-30. doi: 10.1002/jps.10388.
The effect of protein-calorie malnutrition (PCM) on the expression and functional activity of P-glycoprotein (P-gp) in the liver of rats was examined. Control protein diets and protein-restricted diets were fed to Sprague-Dawley rats for 4 weeks, and the expression of P-gp in the liver (Western blot), in vitro uptake of a representative substrate of P-gp, daunomycin, into canalicular liver plasma membrane (cLPM) vesicles, and in vivo canalicular excretion of daunomycin were compared between the control and PCM rats. The expression of P-gp in the cLPM vesicles was decreased (22%, p < 0.05) by PCM. Consistent with this result, the in vitro uptake rate (V(max)) was decreased (35%, p < 0.05) by PCM, with constant affinity (K(m)), for the carrier-mediated uptake of daunomycin into cLPM vesicles, resulting in a 33% (p < 0.05) decrease in the intrinsic uptake clearance (CL(int)). The in vivo canalicular excretion clearance (CL(exc)) of daunomycin was also decreased by 79% (p < 0.01) in PCM rats, but the degree was more severe than would be expected from the 22% decrease in the expression of P-gp and the 33% decrease in the uptake of daunomycin (CL(int)). The hepatic level of adenosine 5'-triphosphate, which was decreased by 60% (p < 0.01) in PCM rats, might have contributed to this severe decrease in CL(exc). In summary, the canalicular excretion of P-gp substrates, such as daunomycin, might be reduced in patients with PCM via a mechanism involving the suppression of the expression of P-gp.
研究了蛋白质 - 热量营养不良（PCM）对大鼠肝脏中P - 糖蛋白（P - gp）表达及功能活性的影响。将对照蛋白质饮食和蛋白质限制饮食喂养Sprague - Dawley大鼠4周，比较对照大鼠和PCM大鼠肝脏中P - gp的表达（蛋白质印迹法）、P - gp代表性底物柔红霉素向胆小管肝细胞膜（cLPM）囊泡的体外摄取以及柔红霉素的体内胆小管排泄情况。PCM使cLPM囊泡中P - gp的表达降低（22%，p < 0.05）。与该结果一致，PCM使柔红霉素载体介导摄取进入cLPM囊泡的体外摄取速率（V(max)）降低（35%，p < 0.05），而亲和力（K(m)）不变，导致内在摄取清除率（CL(int)）降低33%（p < 0.05）。PCM大鼠中柔红霉素的体内胆小管排泄清除率（CL(exc)）也降低了79%（p < 0.01），但其降低程度比根据P - gp表达降低22%和柔红霉素摄取降低33%（CL(int)）所预期的值更为严重。PCM大鼠中三磷酸腺苷的肝脏水平降低了60%（p < 0.01），这可能是导致CL(exc)严重降低的原因。总之，PCM患者中P - gp底物如柔红霉素的胆小管排泄可能通过涉及P - gp表达受抑制的机制而减少。
