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 (30-300 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-(0.375-30 muM) and time-dependent (3-24 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 muM 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 (2S,3S)-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.
Aleo
Michael D
MD
Pfizer Global Research and Development, Groton Laboratories, Safety Sciences, MS 8274-1229, Eastern Point Rd., Groton, CT 06340, USA. michael_d_aleo@groton.pfizer.com
Doshna
Colleen M
CM
Navetta
Kimberly A
KA
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001578:Benzopyrans / Q000633:toxicity; D002386:Cataract / Q000139:chemically induced*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000032:analysis; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000633:toxicity*
D001578:Benzopyrans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000255:Adenosine Triphosphate; C089948:darglitazone; D005978:Glutathione; C039671:ciglitazone; C066021:englitazone