Molecular mechanism of cataractogenesis: III. Toxic metabolites of oxygen as initiators of lipid peroxidation and cataract

Abstract

A free radical mechanism of cataractogenesis involving enzymatic and nonenzymatic reactions, is proposed. Supporting experimental evidence is briefly reviewed. H₂O₂, which is one of the toxic metabolites of oxygen, was significantly increased 2–3 fold in ocular humors in several experimental cataracts and in human senile cataract. Various cataractogenic agents were also found to increase H₂O₂ in ocular humors in vivo prior to cataract formation. Enzymatic defenses against O₂·- and H₂O₂ provided by superoxide dismutase, catalase and glutathione peroxidase were impaired in cataracts. In some cataracts, catalase and superoxide dismutase were affected earlier. Malondialdehyde (MDA), a major breakdown product of lipid peroxides was significantly increased by 2–4-fold in human senile cataract, in cataracts induced in rabbit and rat, and in hereditary cataracts in mice. All the reactive species of O₂ (O₂·-, H₂O₂, OH· and ¹ΔgO₂) may participate in initiating lipid peroxidation of lens in vitro. Various scavengers of these species were capable of preventing lenticular lipid peroxidation, amongst which OH· scavengers were found to be the most effective. Biological antioxidant, vitamin E afforded 44% prevention of lipid peroxidation in lens. The important observation was that vitamin E was therapeutically effective in about 50% of animals in arresting cataract induced in rabbit by 3-aminotriazole. In these rabbits, H₂O₂ and ascorbic acid of ocular humors and MDA of lens were close to normal. It is our working hypothesis that the carbonyl groups of MDA and amino groups of amino acids, proteins, nucleic acids and their bases, and phospholipids could interact in a cross-linking reaction producing high molecular weight aggregates by Schiff-base conjugate formation in addition to disulfide cross-linking of proteins, and finally resulting in cataract.