The Efficacy of Aldose Reductase Inhibitors on Polyol Accumulation in Human Lens and Retinal Pigment Epithelium in Tissue Culture

Venkat N. Reddy, Li Ren Lin, Frank J. Giblin, Marjorie Lou, Peter F. Kador, Jin H. Kinoshita

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The formation of excess sugar alcohol mediated by aldose reductase (AR) and its intracellular accumulation in lens with resultant hydration is thought to be the initiating mechanism in the pathogenesis of diabetic and galactosemic cataracts. AR is also involved in other diabetic complications including retinopathy and neuropathy. Therefore, there is heightened interest in developing effective AR inhibitors (ARIs) fr possble clnica use in human diabetes. However, the evaluation of these drugs for potential clinical use requires that the compounds be evaluated in appropriate target tissues since AR from different tissues is known to exhibit differential susceptibility to ARIs. The relative efficacy of ARIs in human lens epithelium (HLE) and human retinal pigment epithelium (HRPE) was studied by measuring the degree of inhibition of galactitol formation at various concentrations of ARI following incubation of cells in high galactose media for 72 hrs. Regardless of the structural characteristics of the ARIs investigated, higher doses were required to inhibit polyol synthesis in HRPE as compared to HLE c50s. Based on ED<50 values, dose required for 50% inhibition, the order of potencies against both HLE and HRPE enzymes was AL-4114 > AL-3152e> AL-1576 > tolrcstat > statil > sorbinil. Since some ARIs are known to be bound to plasma proteins, it is conceivable that the observed differences in ED50 values could be due to differential binding to serum proteins in the culture medium. This possibility was examined by employing cultures of dog lens epithelium (DLE). These cells, which synthesize much higher levels of galactitol than HLE and HRPE, could e maintaine in serm-free medi for hort peiods (4 hrs) of time. The results, which demonstrate that the extent of polyol inhibition was the same in the presence or absence of serum, suggest that the differences in the potency of the inhibitors may reflect their inherent ativity against AR in HLE and HRPE cells.

Original languageEnglish (US)
Pages (from-to)43-52
Number of pages10
JournalJournal of Ocular Pharmacology
Volume8
Issue number1
DOIs
StatePublished - Jan 1 1992

Fingerprint

Aldehyde Reductase
Retinal Pigment Epithelium
Lenses
Epithelium
Galactitol
Blood Proteins
Sugar Alcohols
polyol
Drug Evaluation
Diabetes Complications
Galactose
Cataract
Culture Media
Dogs

ASJC Scopus subject areas

  • Ophthalmology
  • Pharmacology
  • Pharmacology (medical)

Cite this

The Efficacy of Aldose Reductase Inhibitors on Polyol Accumulation in Human Lens and Retinal Pigment Epithelium in Tissue Culture. / Reddy, Venkat N.; Lin, Li Ren; Giblin, Frank J.; Lou, Marjorie; Kador, Peter F.; Kinoshita, Jin H.

In: Journal of Ocular Pharmacology, Vol. 8, No. 1, 01.01.1992, p. 43-52.

Research output: Contribution to journalArticle

Reddy, Venkat N. ; Lin, Li Ren ; Giblin, Frank J. ; Lou, Marjorie ; Kador, Peter F. ; Kinoshita, Jin H. / The Efficacy of Aldose Reductase Inhibitors on Polyol Accumulation in Human Lens and Retinal Pigment Epithelium in Tissue Culture. In: Journal of Ocular Pharmacology. 1992 ; Vol. 8, No. 1. pp. 43-52.
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