B16 흑색종세포에서 로바스타틴에 의한 멜라닌 합성 촉진효과에 미치는 산화질소의 역할

Role of Nitric Oxide in the Lovastatin-Induced Stimulation of Melanin Synthesis in B16 Melanoma Cells

Previously, we have reported that lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, increased melanin synthesis through intracellular Ca 2+ release in B16 cells. In this study we investigated the possible involvement of nitric oxide (NO) in the mechanism of lovastatin-induced melanogenesis. Lovastatin elevated NO formation in a dose-dependent manner. Treatment with mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), precursors of cholesterol, did not significantly alter the lovastatin-induced NO production, suggesting that inhibition of cholesterol metabolism may not be involved in the mechanism of this action of lovastatin. Both NO formation and melanogenesis induced by lovastatin was significantly suppressed by treatment with N G -nitro-L-arginine methyl ester (L-NAME) and 2-(4-carboxy-2-phe- nyl)-4,4,5,5-tetramethylinidazoline-1-oxyl-3-oxide (cPTIO), an inhibitor of NO synthase and a NO scavenger, espectively. The lov-astatin-induced NO production was significantly affected not by EGTA, an extracellular Ca 2+ chelator, but by an intracellular Ca 2+ chelator (BAPTA/AM) and intracellular Ca2+ release blockers (dantrolene and TMB-8). Taken together, these results suggest that lovastatin may induce melanogenesis through NO formation mediated by intracellular Ca 2+ release in B16 cells. These results fur-ther suggest that lovastatin may be a good candidate for the therapeutic application of various hypopigmentation disorders.