Chinn Leslie W, Gow Jason M, Tse Man Ming, Becker Stephen L, Kroetz Deanna L
Department of Biopharmaceutical Sciences, University of California San Francisco, 1550 4th Street, San Francisco, CA 94158, USA.
J Antimicrob Chemother. 2007 Jul;60(1):61-7. doi: 10.1093/jac/dkm135. Epub 2007 May 17.
ABCB1 encodes the efflux transporter P-glycoprotein (P-gp), which regulates the intracellular concentration of many xenobiotics, including several HIV protease inhibitors (PIs). Exposure to some xenobiotics, such as the antibiotic rifampicin, increases P-gp expression. In the present study, we investigated the effect of the HIV PIs saquinavir and atazanavir on the expression and function of ABCB1 and P-gp in primary and cultured lymphocytes, as well as the molecular interactions between these drugs and P-gp. ABCB1 and P-gp expression and function were examined in lymphocyte samples from healthy subjects before and after atazanavir-boosted saquinavir treatment. Expression and function were also studied in CEM cells following exposure to atazanavir and saquinavir. The inhibitory effects of these drugs were investigated in ABCB1-transfected HEK293T cells.
P-gp expression and function were measured by flow cytometry. ABCB1 mRNA expression was evaluated using quantitative RT-PCR.
There were no overall changes in ABCB1 or P-gp expression or function after saquinavir-atazanavir treatment in primary lymphocyte samples. However, there was considerable interindividual variability in baseline lymphocyte ABCB1 expression, as well as in the degree of change in ABCB1 expression after saquinavir-atazanavir administration. In cell culture, 5 microM saquinavir increased ABCB1 levels, although it did not affect P-gp expression. Atazanavir inhibited P-gp function at concentrations above therapeutic levels.
Differences in lymphocyte ABCB1 expression, which may be caused by genetic polymorphisms in ABCB1 or its regulatory partners, are a likely cause of interindividual variation in the disposition and efficacy of clinically relevant P-gp substrates, including HIV PIs.
ABCB1编码外排转运蛋白P-糖蛋白（P-gp），该蛋白可调节包括多种HIV蛋白酶抑制剂（PIs）在内的许多外源性物质的细胞内浓度。接触某些外源性物质，如抗生素利福平，会增加P-gp的表达。在本研究中，我们调查了HIV蛋白酶抑制剂沙奎那韦和阿扎那韦对原代及培养淋巴细胞中ABCB1和P-gp的表达及功能的影响，以及这些药物与P-gp之间的分子相互作用。在接受阿扎那韦增强的沙奎那韦治疗前后，检测健康受试者淋巴细胞样本中ABCB1和P-gp的表达及功能。还研究了CEM细胞在接触阿扎那韦和沙奎那韦后的表达及功能。在ABCB1转染的HEK293T细胞中研究了这些药物的抑制作用。
通过流式细胞术检测P-gp的表达及功能。使用定量RT-PCR评估ABCB1 mRNA的表达。
在原代淋巴细胞样本中，沙奎那韦-阿扎那韦治疗后ABCB1或P-gp的表达及功能无总体变化。然而，淋巴细胞ABCB1的基线表达以及沙奎那韦-阿扎那韦给药后ABCB1表达的变化程度存在相当大的个体间差异。在细胞培养中，5 microM的沙奎那韦增加了ABCB1水平，尽管它不影响P-gp的表达。阿扎那韦在高于治疗水平的浓度下抑制P-gp功能。
淋巴细胞ABCB1表达的差异可能由ABCB1或其调节伙伴的基因多态性引起，这可能是包括HIV蛋白酶抑制剂在内的临床相关P-gp底物的处置和疗效个体间差异的一个可能原因。
