Bucala R, Manabe S, Urban R C, Cerami A
Exp Eye Res. 1985 Sep;41(3):353-63. doi: 10.1016/s0014-4835(85)80026-9.
Steroid-induced cataracts occur as a consequence of prolonged, therapeutic levels of glucocorticoids. Previous studies have shown that these lens opacities are associated with the occurrence of covalent glucocorticoid-lens protein adducts. In vitro, the glucocorticoid prednisolone nonenzymatically modifies the lysine residues of lens crystallins. This modification increases the reactivity of protein thiols and leads to the formation of high-molecular-weight, disulfide-linked aggregates. Prednisolone-induced aggregates result in an opalescence in the crystallins solution which is reversed by the addition of dithiothreitol. The acetylation of lens proteins prior to incubation inhibits both the incorporation of prednisolone and the development of opalescence. Gel filtration chromatography of the prednisolone lens protein incubations shows that the majority of the protein-incorporated prednisolone is associated with the disulfide-linked complexes. Similar analysis of proteins obtained from a human steroid-induced cataract demonstrates that prednisolone adducts which form in vivo are also present in reducible, high-molecular-weight complexes. These results implicate the nonenzymatic modification of lens crystallins in the cataractogenic effect of glucocorticoids and suggest possible pharmacological strategies in preventing this toxic manifestation of steroid therapy.
类固醇诱导的白内障是长期使用治疗剂量的糖皮质激素所致。先前的研究表明，这些晶状体混浊与共价糖皮质激素-晶状体蛋白加合物的形成有关。在体外，糖皮质激素泼尼松龙可非酶修饰晶状体晶状体蛋白的赖氨酸残基。这种修饰增加了蛋白质硫醇的反应性，并导致形成高分子量的二硫键连接的聚集体。泼尼松龙诱导的聚集体导致晶状体蛋白溶液出现乳光，加入二硫苏糖醇后可逆转。孵育前对晶状体蛋白进行乙酰化处理可抑制泼尼松龙的掺入和乳光的形成。对泼尼松龙与晶状体蛋白孵育产物进行凝胶过滤层析分析表明，大多数与蛋白结合的泼尼松龙与二硫键连接的复合物有关。对取自人类类固醇诱导性白内障的蛋白质进行类似分析表明，体内形成的泼尼松龙加合物也存在于可还原的高分子量复合物中。这些结果表明晶状体晶状体蛋白的非酶修饰在糖皮质激素的致白内障作用中起作用，并提示了预防类固醇治疗这种毒性表现的可能药理学策略。
