Effect of perillic acid, a putative isoprenylation inhibitor, on the cultured rat lens

Previous studies have demonstrated that agents affecting the cholesterol sy nthetic pathway can have cataractogenic effects. We have suggested that opa cification of cultured lenses resulting from exposure to the cholesterol-lo wering agent lovastatin is caused by inhibition of isoprenylation of small GTPases. To test that hypothesis we have investigated the effects of perill ic acid, an agent reported to inhibit isoprenylation, on rat lenses in orga n culture. Perillic acid caused dose and time dependent opacification of cu ltured lenses. While the opacities appeared grossly similar to those produc ed by lovastatin, they differed dramatically when analysed histologically. It also produced marked morphological changes to lens epithelial cells in c ulture. Analysis of small GTPases in the perillic acid treated cells failed to detect any accumulation in the water soluble fraction as would be expec ted if isoprenylation was inhibited. Further, studies on the isoprenylation of radiolabelled isoprenoids into proteins in cultured lenses showed no si gnificant 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 primar y factor in the perillic acid cataract.