Inhibitory effects of four pharmaceutic compounds on human brain aldose reductase

Aldose reductase (EC.1.1.1.21)was prepared and purified from human brain by DEAE-52 cellulose chromato-graphy,PBE-94 chromatofocusing,NADP+-Sepharose 4B affinity chromatography,and Sephadex G-100 gel nitration.The inhibitory effects of four pharmaceutic com-pounds were studied by enzymatic kinetics.The Lineweaver-Burk plots show that sorbinil,alrestatin,tetramethylene glutaric acid,and phenobarbital are noncompetitive inhibitors of human brain aldose reductase.The second plots of sorbinil,alrestatin,and phenobarbital (slope in the Lineweaver-Burk plots against the concentration of inhibitors)are linear.These results indicate that sorbinil,alrestatin,and phenobarbital are the completely noncom-petitive inhibitors of human brain aldose reduc-tase,while tetramethylene glutaric acid is partially noncompetitive inhibitor.The inhibition curves and the inhibition constants of the four compounds indicate that sorbinil is the most effective inhibitor and alrestatin the se-cond most effective.By evaluating its inhibition constant and side effect,it seems that phenobarbital is not recommendable for clinical use as an inhibitor of aldose reductase.