乙醇对 8 种抗逆转录病毒蛋白酶抑制剂与细胞色素 P450 3A4 的光谱结合和抑制的差异作用。
Differential effects of ethanol on spectral binding and inhibition of cytochrome P450 3A4 with eight protease inhibitors antiretroviral drugs.
机构信息
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, 64108, USA.
出版信息
Alcohol Clin Exp Res. 2011 Dec;35(12):2121-7. doi: 10.1111/j.1530-0277.2011.01575.x. Epub 2011 Jun 17.
BACKGROUND
Cytochrome P450 3A4 (CYP3A4) is the most abundant CYP enzyme in the liver, which metabolizes approximately 50% of the marketed drugs including antiretroviral agents. CYP3A4 induction by ethanol and its impact on drug metabolism and toxicity is known. However, CYP3A4-ethanol physical interaction and its impact on drug binding, inhibition, or metabolism is not known, except that we have recently shown that ethanol facilitates the binding of a protease inhibitor (PI), nelfinavir, with CYP3A4. The current study was designed to examine the effect of ethanol on spectral binding and inhibition of CYP3A4 with all currently used PIs that differ in physicochemical properties.
METHODS
We performed type I and type II spectral binding with CYP3A4 at 0 and 20 mM ethanol and varying PIs' concentrations. We also performed CYP3A4 inhibition using 7-benzyloxy-4-trifluoromethylcoumarin substrate and NADPH at varying concentrations of PIs and ethanol.
RESULTS
Atazanavir, lopinavir, saquinavir, and tipranavir showed type I spectral binding, whereas indinavir and ritonavir showed type II. However, amprenavir and darunavir did not show spectral binding with CYP3A4. Ethanol at 20 mM decreased the maximum spectral change (δA(max)) with type I lopinavir and saquinavir, but it did not alter δA(max) with other PIs. Ethanol did not alter spectral binding affinity (K(D)) and inhibition constant (IC(50)) of type I PIs. However, ethanol significantly decreased the IC(50) of type II PIs, indinavir and ritonavir, and markedly increased the IC(50) of amprenavir and darunavir.
CONCLUSIONS
Overall, our results suggest that ethanol differentially alters the binding and inhibition of CYP3A4 with the PIs that have different physicochemical properties. This study has clinical relevance because alcohol has been shown to alter the response to antiretroviral drugs, including PIs, in HIV-1-infected individuals.
背景
细胞色素 P450 3A4（CYP3A4）是肝脏中含量最丰富的 CYP 酶，代谢约 50%的市售药物，包括抗逆转录病毒药物。已知乙醇诱导 CYP3A4，并对药物代谢和毒性产生影响。然而，乙醇与 CYP3A4 的物理相互作用及其对药物结合、抑制或代谢的影响尚不清楚，只是我们最近表明，乙醇促进了蛋白酶抑制剂（PI）奈非那韦与 CYP3A4 的结合。本研究旨在研究乙醇对所有目前使用的 PI 与 CYP3A4 的光谱结合和抑制作用的影响，这些 PI 在物理化学性质上有所不同。
方法
我们在 0 和 20mM 乙醇和不同 PI 浓度下进行 CYP3A4 的 I 型和 II 型光谱结合。我们还使用 7-苄氧基-4-三氟甲基香豆素底物和 NADPH，在不同浓度的 PI 和乙醇下进行 CYP3A4 抑制。
结果
阿扎那韦、洛匹那韦、沙奎那韦和替拉那韦显示 I 型光谱结合，而茚地那韦和利托那韦显示 II 型。然而，安普那韦和达芦那韦与 CYP3A4 没有显示光谱结合。20mM 乙醇降低了 I 型洛匹那韦和沙奎那韦的最大光谱变化（δA(max)），但不改变其他 PI 的δA(max)。乙醇不改变 I 型 PI 的光谱结合亲和力（K(D)）和抑制常数（IC(50)）。然而，乙醇显著降低了 II 型 PI 茚地那韦和利托那韦的 IC(50)，并显著增加了安普那韦和达芦那韦的 IC(50)。
结论
总的来说，我们的结果表明，乙醇以不同的方式改变了具有不同物理化学性质的 PI 与 CYP3A4 的结合和抑制。这项研究具有临床相关性，因为已经表明，酒精会改变 HIV-1 感染个体对抗逆转录病毒药物（包括 PI）的反应。
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