The role of lens protein glycation, oxidation and enzyme inactivation in cataract formation

Abstract

Cataract is a multifactorial disease responsible for approximately 40-50% of all reported cases of blindness and visual impairment throughout the world. While it is essentially an age dependent phenomenon, cataract formation is accelerated in certain metabolic diseases, especially in diabetes. Therefore a study of the biochemistry of cataract formation in diabetic conditions is considered useful for understanding the mechanism of this visual impairment in general. The present study was to ascertain the damaging effect of oxidation and glycation on the structural as well as functional integrity of certain crystallins and enzymes involved in the maintenance of lens clarity and to examine the effect of pyruvate and other primary antioxidant enzymes against such damage. It has been found that enzymes, such as glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, catalase and superoxide dismutase, incubated with fructose at levels prevalent in the diabetic lens leads to a significant loss of activities. Interestingly, the glycation and consequent formation of advanced glycation end (AGE) products from alpha-crystallin by incubation with fructose was more pronounced than beta, and gamma-crystallins. All these changes in the structure and function of proteins induced by fructose were prevented by pyruvate. The protective effect is attributable to pyruvate's ability to competitively inhibit glycation as well as to its activity of scavenging reactive oxygen species (ROS). In order to understand the pathophysiologic and pharmacologic significance of these findings in vivo, further studies were conducted with rats made diabetic with streptozotocin. The results show that exogenous administration of pyruvate to such animals decreased the extent of several biochemical changes known to participate in cataract formation, such as the elevation in the levels of glycated proteins, sorbitol, lipid peroxidation and the loss of permeability functions indexed by the decrease in the transport of sodium and potassium ions. The progress of cataract was also significantly delayed. Hence, the study suggests that pyruvate is an effective agent against the early metabolic as well as the late phases of the reactions associated with the formation of cataracts, exerting an overall protective effect against cataract formation induced by the hyperglycemia.