Batuman V, Chadha I
Renal Section, Veterans Affairs Medical Center, East Orange, NJ 07019.
Life Sci. 1990;47(14):1187-93. doi: 10.1016/0024-3205(90)90210-i.
To investigate the pathogenetic mechanisms of interferon nephrotoxicity, we studied the effect of recombinant interferon alfa-2b on the uptake of 14C-D-glucose and 14C-L-alanine by rat renal brush-border-membrane vesicles. Interferon significantly inhibited 20 sec. sodium-dependent and 5 and 10 min. equilibrium uptake of both glucose and alanine. The inhibitory effect was dose dependent with maximum effect achieved at interferon concentration of 5 X 10(-8)M in the uptake media. The half-maximal inhibitory concentrations, IC50, of interferon on glucose uptake was 1.8 X 10(-8)M, and 5.4 X 10(-9)M on alanine uptake. Dixon plot analysis of uptake data was consistent with pure non-competitive inhibition. The inhibition constants, Ki, 1.5 X 10(-8)M for glucose uptake, and 7.3 X 10(-9)M for alanine uptake, derived from Dixon plots were in close agreement with the IC50s calculated from the semilog dose response curves. These observations reveal that direct interactions at the proximal tubule cell membrane are involved in the pathogenesis of interferon nephrotoxicity, and that its mechanism of nephrotoxicity is similar to that of other low molecular weight proteins.
为了研究干扰素肾毒性的发病机制，我们研究了重组干扰素α-2b对大鼠肾刷状缘膜囊泡摄取14C-D-葡萄糖和14C-L-丙氨酸的影响。干扰素显著抑制了20秒时钠依赖性葡萄糖和丙氨酸的摄取以及5分钟和10分钟时的平衡摄取。抑制作用呈剂量依赖性，在摄取培养基中干扰素浓度为5×10^(-8)M时达到最大效应。干扰素对葡萄糖摄取的半数最大抑制浓度（IC50）为1.8×10^(-8)M，对丙氨酸摄取的IC50为5.4×10^(-9)M。摄取数据的Dixon图分析与纯粹的非竞争性抑制一致。从Dixon图得出的葡萄糖摄取抑制常数（Ki）为1.5×10^(-8)M，丙氨酸摄取的Ki为7.3×10^(-9)M，与从半对数剂量反应曲线计算出的IC50非常一致。这些观察结果表明，近端肾小管细胞膜上的直接相互作用参与了干扰素肾毒性的发病机制，并且其肾毒性机制与其他低分子量蛋白质的相似。
