Cook P N, Ward W H, Petrash J M, Mirrlees D J, Sennitt C M, Carey F, Preston J, Brittain D R, Tuffin D P, Howe R
ZENECA Pharmaceuticals, Macclesfield, Cheshire, U.K.
Biochem Pharmacol. 1995 Apr 18;49(8):1043-9. doi: 10.1016/0006-2952(95)98499-y.
Aldose reductase (aldehyde reductase 2) catalyses the conversion of glucose to sorbitol, and methylglyoxal to acetol. Treatment with aldose reductase inhibitors (ARIs) is a potential approach to decrease the development of diabetic complications. The sulphonylnitromethanes are a recently discovered class of aldose reductase inhibitors, first exemplified by ICI215918. We now describe enzyme kinetic characterization of a second sulphonylnitromethane, 3',5'-dimethyl-4'-nitromethylsulphonyl-2-(2-tolyl)acetanilide (ZD5522), which is at least 10-fold more potent against bovine lens aldose reductase in vitro and which also has a greater efficacy for reduction of rat nerve sorbitol levels in vivo (ED95 = 2.8 mg kg-1 for ZD5522 and 20 mg kg-1 for ICI 215918). ZD5522 follows pure noncompetitive kinetics against bovine lens aldose reductase when either glucose or methylglyoxal is varied (K(is) = K(ii) = 7.2 and 4.3 nM, respectively). This contrasts with ICI 215918 which is an uncompetitive inhibitor (K(ii) = 100 nM) of bovine lens aldose reductase when glucose is varied. Against human recombinant aldose reductase, ZD5522 displays mixed noncompetitive kinetics with respect to both substrates (K(is) = 41 nM, K(ii) = 8 nM with glucose and K(is) = 52 nM, K(ii) = 3.8 nM with methylglyoxal). This is the first report of the effects of a sulphonylnitromethane on either human aldose reductase or utilization of methylglyoxal. These results are discussed with reference to a Di Iso Ordered Bi Bi mechanism for aldose reductase, where the inhibitors compete with binding of both the aldehyde substrate and alcohol product. This model may explain why aldose reductase inhibitors follow noncompetitive or uncompetitive kinetics with respect to aldehyde substrates, and X-ray crystallography paradoxically locates an ARI within the substrate binding site. Aldehyde reductase (aldehyde reductase 1) is closely related to aldose reductase. Inhibition of bovine kidney aldehyde reductase by ZD5522 follows uncompetitive kinetics with respect to glucuronate (K(ii) = 39 nM), indicating a selectivity greater than 5-fold for bovine aldose reductase relative to aldehyde reductase.
醛糖还原酶（醛还原酶2）催化葡萄糖转化为山梨醇，以及甲基乙二醛转化为丙酮醇。用醛糖还原酶抑制剂（ARIs）进行治疗是一种降低糖尿病并发症发生风险的潜在方法。磺酰基硝基甲烷是最近发现的一类醛糖还原酶抑制剂，首个实例为ICI215918。我们现在描述了第二种磺酰基硝基甲烷3',5'-二甲基-4'-硝基甲基磺酰基-2-(2-甲苯基)乙酰苯胺（ZD5522）的酶动力学特征，它在体外对牛晶状体醛糖还原酶的抑制效力至少高10倍，并且在体内降低大鼠神经中山梨醇水平的效果也更好（ZD5522的ED95 = 2.8 mg kg-1，ICI 215918的ED95 = 20 mg kg-1）。当改变葡萄糖或甲基乙二醛的浓度时，ZD5522对牛晶状体醛糖还原酶呈现纯非竞争性动力学（K(is) = K(ii)分别为7.2和4.3 nM）。这与ICI 215918形成对比，当改变葡萄糖浓度时，ICI 215918是牛晶状体醛糖还原酶的非竞争性抑制剂（K(ii) = 100 nM）。对于人重组醛糖还原酶，ZD5522对两种底物均呈现混合型非竞争性动力学（以葡萄糖为底物时，K(is) = 41 nM，K(ii) = 8 nM；以甲基乙二醛为底物时，K(is) = 52 nM，K(ii) = 3.8 nM）。这是关于磺酰基硝基甲烷对人醛糖还原酶或甲基乙二醛利用影响的首次报道。这些结果结合醛糖还原酶的双底物双产物有序动力学机制进行了讨论，在该机制中，抑制剂与醛底物和醇产物的结合相互竞争。该模型或许可以解释为何醛糖还原酶抑制剂对醛底物呈现非竞争性或反竞争性动力学，以及X射线晶体学为何反常地在底物结合位点内定位到一种ARI。醛还原酶（醛还原酶1）与醛糖还原酶密切相关。ZD5522对牛肾醛还原酶的抑制作用相对于葡萄糖醛酸呈现反竞争性动力学（K(ii) = 39 nM），表明相对于醛还原酶，其对牛醛糖还原酶的选择性大于5倍。
