Effect of perillic acid, a putative isoprenylation inhibitor, on the cultured rat lens.
Previous studies have demonstrated that agents affecting the cholesterol synthetic pathway can have cataractogenic effects. We have suggested that opacification of cultured lenses resulting from exposure to the cholesterol-lowering agent lovastatin is caused by inhibition of isoprenylation of small GTPases. To test that hypothesis we have investigated the effects of perillic acid, an agent reported to inhibit isoprenylation, on rat lenses in organ culture. Perillic acid caused dose and time dependent opacification of cultured lenses. While the opacities appeared grossly similar to those produced by lovastatin, they differed dramatically when analysed histologically. It also produced marked morphological changes to lens epithelial cells in culture. Analysis of small GTPases in the perillic acid treated cells failed to detect any accumulation in the water soluble fraction as would be expected if isoprenylation was inhibited. Further, studies on the isoprenylation of radiolabelled isoprenoids into proteins in cultured lenses showed no significant decrease following perillic acid exposure. It was concluded that perillic acid causes cataract in this system by a mechanism different from lovastatin and that inhibition of isoprenylation is unlikely to be a primary factor in the perillic acid cataract.
Cheng
Q F
QF
Laboratory of Mechanisms of Ocular Diseases, National Eye Institute, 6 Center Drive, MSC 2735, Bethesda, MD 20892, USA.
Rao
P V
PV
Zigler
J S
JS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002386:Cataract / Q000139:chemically induced* / Q000473:pathology; D053138:Cyclohexenes; D004224:Diterpenes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005204:Farnesol / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000032:analysis; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D039821:Monoterpenes; D009924:Organ Culture Techniques; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D053138:Cyclohexenes; D004224:Diterpenes; D039821:Monoterpenes; D013729:Terpenes; D005204:Farnesol; C078706:perillic acid; D008148:Lovastatin; C017338:geranylgeraniol; D020558:GTP Phosphohydrolases