Ciglitazone-Induced Lenticular Opacities in Rats: In Vivo and Whole Lens Explant Culture Evaluation
The cataractogenic potential of the thiazolidinedione ciglitazone (CIG) was investigated in vivo and in vitro. In the rat, CIG caused a dose-dependent (30â300 mg/kg/day) increase in incidence and severity of nuclear cataract formation during a 3-month nonclinical safety assessment study. Potential...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 312; no. 3; pp. 1027 - 1033 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.03.2005
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Subjects | |
Online Access | Get full text |
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Summary: | The cataractogenic potential of the thiazolidinedione ciglitazone (CIG) was investigated in vivo and in vitro. In the rat,
CIG caused a dose-dependent (30â300 mg/kg/day) increase in incidence and severity of nuclear cataract formation during a 3-month
nonclinical safety assessment study. Potential mechanisms of toxicity were surveyed using whole rat lens explants exposed
to CIG with or without various inhibitors of cataract formation. In vitro, CIG caused a concentration-(0.375â30 μM) and time-dependent
(3â24 h) change in biochemical [ATP content or mitochondrial reduction of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
(MTT) and reduced glutathione (GSH) content] and morphometric (lens wet weight and clarity) markers of damage. Within 3 h
of exposure, 7.5 μM CIG decreased lens ATP content 37 ± 7% (percentage of difference from control, p < 0.05). After 24 h of exposure, lens ATP content, MTT reduction, and GSH content declined 57 ± 5, 30 ± 28, and 42 ± 8%,
respectively. Lens wet weight increased 17 ± 4% with a concomitant decrement in lens clarity. Pretreating lenses with the
mitochondrial calcium uniport inhibitor ruthenium red (RR) partially or fully protected lenses from toxicity. In contrast,
the antioxidant dithiothreitol, aldose reductase inhibitor sorbinil, and selective cell-permeable calpain inhibitors [calpain
II inhibitor and (2 S ,3 S )- trans -epoxysuccinyl- l -leucylamido-3-methylbutane ethyl ester (E64d)] were ineffective in providing protection under the present testing conditions.
Early and selective changes in lenticular ATP content and the partial or full protective effect of RR suggest that alterations
in lens bioenergetics may play an important role in CIG-induced cataract formation. Lens explant cultures were successfully
used to select two thiazolidinediones that lacked cataractogenic activity when evaluated in 3-month rat safety assessment
studies. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.104.076950 |