The use of explant lens culture to assess cataractogenic potential.
Explanted cultures of crystalline lenses have been used to investigate mechanisms of xenobiotic-induced cataract formation. However, very few studies have utilized mechanistic information to predict the cataractogenic potential of structurally diverse xenobiotics. The present investigation outlines how visual assessment of lens clarity, biochemical endpoints of toxicity, and mechanisms of lenticular opacity formation can be used to select compounds with a lower probability of causing cataract formation in vivo. The rat lens explant culture system has been used to screen thiazolidinediones against ciglitazone for their direct cataractogenic potential in vitro. The two compounds that were selected as development candidates (englitazone and darglitazone) did not produce cataracts in rats exposed daily for 3 months. The culture system has also been used to illustrate that the lens is capable of metabolizing compounds to reactive intermediates. In this example, the toxicity of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a model cataractogen, was attenuated by inhibiting lenticular cysteine conjugate beta-lyase metabolism using aminooxyacetic acid. Finally, this model was used retrospectively to investigate the cataractogenic potential of CJ-12,918 and CJ-13,454 in rats. These compounds showed differences in the incidence of cataract formation in vivo based on differences in hepatic metabolism and penetration of parent drug and metabolites into the lens. The rank order of cataractogenic potential in vitro correlated better with in vivo results when an induced S9 microsomal fraction was added to the culture media. However, the model did not correctly predict the cataractogenic potential of ZD2138, a structurally similar compound. These studies illustrate the use of explant culture to assess mechanisms of cataract formation and outline its use and limitations for predicting cataractogenic potential in vivo.
Aleo
M D
MD
Drug Safety Evaluation, Pfizer Central Research, Groton, Connecticut 06340, USA. Michael_D_Aleo@groton.pfizer.com
Avery
M J
MJ
Beierschmitt
W P
WP
Drupa
C A
CA
Fortner
J H
JH
Kaplan
A H
AH
Navetta
K A
KA
Shepard
R M
RM
Walsh
C M
CM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D002386:Cataract / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D007908:Lens, Crystalline / Q000187:drug effects / Q000473:pathology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D045162:Thiazolidinediones; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D001578:Benzopyrans; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D045162:Thiazolidinediones; D015262:Xenobiotics; D000625:Aminooxyacetic Acid; D000255:Adenosine Triphosphate; C089948:darglitazone; D005978:Glutathione; C039671:ciglitazone; C066021:englitazone