Purpose: To investigate the detoxification mechanisms of the most toxic lipid aldehyde, 4-hydroxynonenal (HNE) and its role in hyperglycemic cataract. Methods: HNE conjugates with GSH spontaneously or catalysed by glutathione S-transferases. Reduction of HNE and HNE-GS conjugate by homogenous preparation of bovine lens aldose reductase (AR) was studied. In-vitro cataracts were developed by culturing rat lenses in 50 mM glucose or 50 μM HNE. Antioxidant, trolox (100 μM) and AR inhibitor, sorbinil (50 μM) were also included in some cultures. Lenticular opacification was assessed by digital image analysis. Results: Lens AR efficiently reduced HNE and HNE-GS in the presence of NADPH (Km HNE ≃ 9 μM; Km HNE-GS ≃ 30 μM). In lenses cultured under hyperglycemic conditions, both trolox and sorbinil had protective effect as reported. In lenses cultured with HNE, the decrease in transmitted light was 43, 65, and 87% on days 3, 5, and 8, respectively. Trolox ameliorated whereas sorbinil accelerated the progression of HNE catarat. Conclusions: (1) HNE and HNE-GS are excellent substrates for AR, (2) HNE is cataractogeneic; antioxidant ameliorates the cataractogenic effect of glucose and HNE, possibly by stabilizing the membrane and increasing the antioxidation capacity of the lens (3) Sorbinil ameliorates the cataractogenic effect of glucose by inhibiting AR and sparing NADPH which would increase the antioxidant capacity and (4) HNE-cataract is accelerated by sorbinil because it inhibits AR-mediated HNE detoxification.
|Original language||English (US)|
|Journal||Investigative Ophthalmology and Visual Science|
|State||Published - Feb 15 1996|
ASJC Scopus subject areas
- Sensory Systems
- Cellular and Molecular Neuroscience