Fructose induced deactivation of glucose-6-phosphate dehydrogenase activity and its prevention by pyruvate: Implications in cataract prevention

Glucose-6-phosphate dehydrogenase (G6PDH) is an important lens enzyme diver ting about 14% of the tissue glucose to the hexose monophosphate shunt path way. The main function of such a pronounced activity of the enzyme is to su pport reductive biosyntheses, as well as to maintain a reducing environment in the tissue so as to prevent oxy-radical induced damage and consequent c ataract formation. Sugars are one of the well-known cataractogenic agents. Several reports suggest that the cataractogenic effect of the sugars in dia betes as well as in normal aging is initiated by the glycation of the prote ins including the enzymes and subsequent formation of more complex and biol ogically inactive or harmful structures. In a diabetic lens the concentrati on of fructose exceeds significantly the concentration of glucose, suggesti ng that the contribution of fructosylation may be greater than that of gluc osylation. These studies were undertaken to examine further the possibility that in addition to glycation, generation of oxygen free radicals by fruct ose and consequent oxidative modifications in certain enzymes may be an imp ortant participant in the cataractogenic process. This hypothesis was teste d by using G6PDH. The enzyme was incubated with various levels of fructose (0-20 mM) and its activity determined as a function of time. This led to a significant loss of its activity, which was prevented by superoxide dismuta se, catalase, mannitol and myoinositol. Most interestingly, pyruvate at lev els between 0.2 and 1.0 mM also offered substantial protection. Hence, the results, while elucidating further the mechanism of enzyme deactivation by sugars such as fructose, also demonstrate the possibility of therapeutic pr evention of cataracts by pyruvate and other such keto acids, in diabetes an d other disabilities involving oxygen free radicals in the pathogenetic pro cess.