Inhibition of Human Aldose and Aldehyde Reductases by Non-Steroidal Anti-Inflammatory Drugs

Abstract

Aldose reductase (EC 1.1.1.21; alditol:NAD(P)+oxidoreductase; ALR2), a member of the multi gene family of NADPH-dependent aldo-keto reductases, is one of the major enzymes implicated in the intracellular events leading to the development of diabetic complications. ALR2 catalyzes the reduction of glucose to sorbitol in the first reaction of the polyol pathway which may be important under conditions of hyperglycemia (Kador and Kinoshita, 1985). There have been a number of reports that some non-steroidal anti-inflammatory drugs (NSAIDs) can delay the development of diabetic complications. These reports include in vitro studies with isolated lens or nerve tissue (Chaudhry et al., 1983; Sharma and Cotlier, 1982; Crabbe et al., 1985; Jacobson et al., 1983), animal studies (Gupta and Joshi, 1991a; Blakytny and Harding, 1992; Gupta and Joshi, 1991b; Mansour et al., 1990; Sharma et al., 1989a), and clinical studies (Sharma et al., 1989b; Cunha-Vaz et al., 1985; Cohen and Harris, 1987). Several NSAIDs have been shown to be inhibitors of ALR2 (Chaudhry et al., 1983; Sharma and Cotlier, 1982; Crabbe et al., 1985; Gupta and Joshi, 1991a; Gupta and Joshi, 1991b). Most studies of inhibition of ALR2 by NSAIDs have used either animal ALR2 or crude homogenates of human tissues (Sharma and Cotlier, 1982; Crabbe et al., 1985; Gupta and Joshi, 1991a; Gupta and Joshi, 1991b). There are marked differences in the inhibitor-binding properties of ALR2 from various sources (Kador et al., 1980). In addition, we have shown that human ALR2 can be oxidized easily, resulting in the formation of a form of ALR2 with markedly altered kinetic properties (Vander Jagt et al., 1990a). There is also the problem that crude homogenates generally contain a mixture of ALR2 and the immunochemically distinct, but kinetically related, aldehyde reductase, ALR1 (Vander Jagt et al., 1990b).