Physiological relevance of aldehyde reductase and aldose reductase gene expression.

Abstract

Carbonyl compounds which are produced as intermediate metabolism during ordinary metabom or are present in food or drugs are known to be toxic to living organisms because of their high degree of reactivity. It has also been suggested that elevation in protein carbonyl groups is also a likely cause of aging (Stadtman, 1992). Cells contain defense systems against these compounds (Flynn, 1982) in the form of aldo-keto reductases, which includle aldehyde and aldose reductases, which catalyze the reduction of a variety of aldehydes to alcohols in an NADPH-dependent manner (Jez et al., 1997). Cytotoxic compounds which tain an aldehyde moiety, such as tripeptidyl aldehyde (Inoue et al., 1993),trioses (Van der Jagt et al., 1992) and methotrexate (Callahan and Beverley, 1992) are deified by enzymes in this gene family. The glycation reaction represents another source carbonyl compounds. This reaction occurs during normal aging and at accelerated rates diabetes, and is involved in the pathogenesis of diabetic complications (Fujii et al. 998). Glycation alters the activity of some enzymes such as Cu,Zn-SOD (Arai et al., 1; Ookawara et al., 1992), carbonic anhydrase (Kondo et al., 1987), sorbitol dehy- drogen (Hoshi et al., 1996), and aldehyde reductase (Takahashi et al., 1995b), and is also involved in production of dicarbonyl compounds such as 3-deoxyglucosone and methyloxal (Figure 1). The cross-linking of long-lived proteins such as collagen and lens crystallins are induced by these compounds and correlates with aging and diabetes. These dicarbonyl compounds are highly toxic and induce apoptosis in susceptible cells (Okado al., 1996). The production of aldehydes is enhanced during pathological conditions, includ diabetes and cancer. Concomitantly, aldehyde-reducing activity is also increased in hepatoma cell lines (Canuto et al., 1994). This is mainly due to an elevated expresn of the aldose reductase gene (AKR1B) as has been demonstrated in chemically induceepatoma tissues (Zeindl-Eberhart et al., 1994; Takahashi et al., 1995a).