Nonenzymatic addition of glucocorticoids to lens proteins in steroid-induced cataracts.

Abstract

A bt~stract. A frequent manifestation of longterm glucocorticoid administration is the occurrence of posterior subcapsular cataracts. The molecular basis for this effect has not yet been elucidated. The addition of prednisolone to the rat lens in culture results in a timeand concentration-dependent lens opacification that correlates with the formation of covalent prednisolone-lens protein adducts. Prednisolone adduct formation was analyzed by [3H]prednisolone incorporation and by immunoprecipitation with antiserum specific for proteins modified by the nonenzymatic addition of prednisolone.In the rat lens, these adducts were localized in both the water-soluble and urea-soluble lens protein fractions. Gel electrophoresis and fluorography revealed that the most extensively modified proteins were two crystallins subunits. Lens proteins from 33 normal and cataractous human lenses were fractionated and analyzed for the presence of prednisolone-protein adducts by competitive radioimmunoassay. Adducts were detected only in those samples derived from glucocorticoid-induced cataractous lenses. We conclude that elevated glucocorticoid levels lead to the formation of glucocorticoid-lens protein adducts both in vitro and in vivo. Lens protein modification by glucocorticoids may lead to sufficient biochemical or structural alterations so as to result in cataract formation. The ability of glucocorticoids to form adducts with proteins in vivo also may play a role in some of the other toxic manifestations of long-term glucocorticoid therapy.

Efeitos sistêmicos e síndrome de retirada em tomadores crônicos de corticosteróides

“…A longo prazo e em altas doses, pode ocorrer a ligação covalente dos esteróides às proteínas do cristalino, induzindo a formação de catarata 40,41 .…”

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review

“…Arachidonic Acid (C) It has been reported by Manabe et al [23] that the mechanism of steroid-induced cataract formation is chemically based and possibly not related to the downstream effects of glucocorticoid receptor (GR) activation. At present the most accepted hypothesis of this mechanism is likely to involve non-enzymatic formation of Schiff base intermediates between the steroid C-20 ketone group and nucleophilic groups such as  -amino groups of lysine residues of proteins (Figure 1).…”

“…At present the most accepted hypothesis of this mechanism is likely to involve non-enzymatic formation of Schiff base intermediates between the steroid C-20 ketone group and nucleophilic groups such as  -amino groups of lysine residues of proteins (Figure 1). Schiff base formation is followed by a Heyns rearrangement [23] involving the nearby C-21 hydroxyl group of the glucocorticoid molecule furnishing stable amine-linked adducts. This covalent binding results in the destabilization of the protein structure allowing further oxidation leading to steroid-induced cataract formation [23].…”

“…Schiff base formation is followed by a Heyns rearrangement [23] involving the nearby C-21 hydroxyl group of the glucocorticoid molecule furnishing stable amine-linked adducts. This covalent binding results in the destabilization of the protein structure allowing further oxidation leading to steroid-induced cataract formation [23]. Figure 1.…”

Corticosteróides sistêmicos na prática dermatológica. Parte I: Principais efeitos adversos

“…A longo prazo e em altas doses, pode ocorrer a ligação covalente dos esteróides às proteínas do cristalino, induzindo a formação de catarata. [43][44][45] Neurológicos: inicialmente os corticosterói-des em excesso causam euforia. Com a exposição prolongada, há uma variedade de anormalidades psicológicas, incluindo irritabilidade, labilidade emocional e depressão.…”