LOVASTATIN ENHANCES THE PHOTOCYTOTOXICITY OF UVA RADIATION TOWARDS CULTURED NCTC-2544 HUMAN KERATINOCYTES - PREVENTION BY CHOLESTEROL SUPPLEMENTATION AND BY A CATHEPSIN INHIBITOR

The effect of the hydroxymethylglutaryl-CoA (HMG-CoA) inhibitor lovast atin on the WA-induced photocytotoxicity has been investigated in cult ured human N.C.T.C. 2544 keratinocytes. In the absence of irradiation, 5 x 10(-7) M lovastatin did not exhibit any significant cytotoxic eff ect towards this cell line. Although the drug cannot act as a photosen sitizer, because it does not absorb in the WA range, it markedly incre ased the UVA-induced cellular damage (about 70% reduction in cell viab ility at 5 x 10(-7) M). This effect was not accompanied by an increase in the lipid peroxidation product content of cells as compared with t reatment with WA alone. Medium supplementation with 0.01 mg/ml free ch olesterol totally prevented the enhancement of UVA photocytotoxicity i nduced by lovastatin. A protective effect was also observed when cells were supplemented with an amount of low-density lipoprotein giving th e same cholesterol concentration in the culture medium. Finally, E64 s -epoxysuccinyl-leucylamido-(4-guanidino)-butane], a lysosomal cathepsi n inhibitor, also prevents the cell death induced by UVA in cells trea ted with lovastatin. These results suggest that HMG-CoA reductase inhi bitors could increase the sensitivity of skin cells to UVA radiation, and that this phenomenon is related to lysosomal enzyme release.