Polyol Accumulation in Galactosemic and Diabetic Rats: Control by an Aldose Reductase Inhibitor

Abstract

An orally active inhibitor of aldose reductase, 1,3-dioxo-1H-benz[de]-isoquinoline-2(3H)acetic acid (AY-22,284), prevented cataractous changes in cultured lenses exposed to high concentrations of galactose. When given orally, AY-22,284 markedly decreased the accumulation of polyols in the lenses and sciatic nerves of galactosemic rats and rats with streptozotocin-induced diabetes. In addition, treatment of galactosemic rats with AY-22,284 effectively suppressed the formation of cataracts.

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…Because of its potential role in mediating hyperglycemic injury and in the development of secondary diabetic complications, (Dvornik et al, 1973;Gabbay et al, 1966) AKR1B1 is by far the most studied AKR. The enzyme was first isolated as a glucose-reducing activity (HERS, 1960).…”

“…Under basal conditions, it catalyzes the reduction of low amounts of glucose. The increase in glucose reduction by AKR1B1 during hyperglycemia has been linked to the development of tissue injury and inhibition of this enzyme has been shown to prevent, delay, or in some cases even reverse, tissue injury associated with diabetes (Gabbay, 2004;Dvornik et al, 1973;Nicolucci et al, 1996;Bril and Buchanan, 2006). Although widespread clinical use of AKR1B1 inhibitors is limited by off-target effects of these drugs, that AR-mediated catalysis represents a significant biochemical cause of hyperglycemic injury is well established (Kinoshita, 1990).…”

Molecular Structure of Human Galactokinase

“…These cells have unusually high levels of the enzyme aldose reductase, which catalyzes the conversion of the sugar to its corresponding sugar alcohol galactitol (dulcitol) in the case of galactosemics and sorbitol in the case of diabetics (11,12). Although the sugar can be transported across the cell membrane, the sugar alcohol cannot (13)(14)(15). Therefore, it accumulates and increases the osmotic potential drawing in water.…”

Inhibitory action on aldose reductase by soybean flavonoids

“…In the lenses of di a betic rats the con tent of sorbitol may be as high as 50 µmol/g, while in the lenses of galactosemic rats, the level of dulcitol can rise to ap prox i mately 80 µmol/g wet weight tis sue 4 . It has been dem on strated that cat a ract forma tion ceases un der the sys temic ad min is tra tion of aldose reductase in hib i tors 7,8 . In or der to solve this prob lem several com pounds have been tested 6,8,9,10 , be sides flavonoids 1,3 .…”

“…It has been dem on strated that cat a ract forma tion ceases un der the sys temic ad min is tra tion of aldose reductase in hib i tors 7,8 . In or der to solve this prob lem several com pounds have been tested 6,8,9,10 , be sides flavonoids 1,3 . The pur pose of the pres ent study is to iso late, pu rify and iden tify flavonoidic com pounds of the UFV-5' soy bean's cultivar, as well as to test their in hib i tory ac tion in aldose reductase in vi tro .…”