Lens cholesterol biosynthesis inhibition: A common mechanism of cataract formation in laboratory animals by pharmaceutical products

• Published in: Journal of applied toxicology 2019-09, Vol.39 (9), p.1348-1361
• Main Authors: Aleo, Michael D., Doshna, Colleen M., Baltrukonis, Daniel, Fortner, Jay H., Drupa, Cynthia A., Navetta, Kimberly A., Fritz, Carol A., Potter, David M., Verdugo, Maria E., Beierschmitt, William P.
• Format: Article
• Language: English
• Subjects: 5‐LO inhibitors; Antagonists; Bioassays; Biosynthesis; cataract; Cataracts; Cholesterol; cholesterol biosynthesis; Desaturase; Dogs; dopamine receptor antagonists, subtype 4 (D4); explant rat lens; Galactose; Incidence; Inhibition; Inhibitors; Laboratory animals; Laboratory tests; Lenses; Liability; Lipoxygenase; Naphthalene; neuronal nitric oxide synthase (nNOS) inhibitor; Nitric oxide; Nitric-oxide synthase; Organic chemistry; peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ); Pharmaceuticals; Safety; Sorbitol; sorbitol dehydrogenase inhibitor (SDI); Squalene; squalene synthetase inhibitor (SSI); stearoyl‐CoA desaturase‐1 (SCD‐1) inhibitor; Tamoxifen; Toxicity
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.3822

CJ‐12,918, a 5‐lipoxygenase (5‐LO) inhibitor, caused cataracts during a 1‐month safety assessment studies in rats whereas the structurally similar ZD‐2138 was without effect. For CJ‐12,918 analogs, blocking different sites of metabolic liability reduced (CJ‐13,454) and eliminated (CJ‐13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD‐2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanism‐based screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ‐12,918 inhibited lens cholesterol biosynthesis (LCB). A 2‐day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5‐LO inhibitors. Thereafter, this 2‐day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl‐CoA desaturase‐1 inhibitors/D4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH‐6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1 month. Spanning two decades, this work shows that lens cholesterol biosynthesis inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was associated with cataract formation in safety assessment studies conducted in rat and dog that were ≥1 month. Cataracts were found in seven programs and include comparisons between compound pairs that did not cause cataracts. This information lays a foundation for future human risk assessment work for cataract formation in animal studies.