TOXIC METABOLITES OF OXYGEN IN CATARACTOGENESIS

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As stated in the earlier report, our overall objective is to investigate molecular mechanisms of cataractogenesis and to search for medical therapy which may prevent or arrest cataract at an early stage. Our studies on cataract induced by 3-amino-1H-1,2,4-triazole, human senile cataract, and selenium-induced cataract strongly suggest that toxic oxygen metabolites, such a O2, H2O2, OH and/or 1O2 are triggering agents in cataractogenesis. The enzymatic defenses provided by catalase, superoxide dismutase (SOD), and GSH peroxidase of lens and other eye tissue against the toxic derivatives of oxygen are of utmost importance in protecting the crystalline lens from oxidative damage. As seen from our recent experimental work, H2O2 of aqueous humor was significantly increased and the activities of lenticular catalase and SOD were decreased in selenium-induced cataract in rat, showing the involvement of similar biochemical mechanism. A fall in the protein-SH of lens showed oxidation of protein and a rise in lenticular malondialdehyde (MDA) evidenced peroxidation of membrane lipids. Cataract induced by selenium may arise from conformational changes in functional and structural proteins of lens due to the formation of disulfide and selenotrisulfide crosslinks by reaction of SH-groups with selenite. We propose to explore these reactions. It is one of our objectives to investigate the possibility of the involvement of similar biochemical mechanism in various experimental cataracts induced by UV, X-ray, naphthalene etc. Further experimental work will be conducted to study the products formed by reaction between MDA and lenticular proteins and amino acids in relation to crosslinking and aggregation. Functional integrity of lens plasma membrane in cataract will be assessed by studying cation transport and amino acid transport. Biosynthesis of protein in cataract will be examined by estimating the incorporation of 14C-L-leucine into lenticular protein. We will also continue the attempts to prevent or arrest cataract in animal model by using antioxidants.