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The tyrosinase inhibitory and antioxidant activities of four nicotinic acid derivatives, namely, nicotinamide, methyl nicotinate, nicotinic acid hydroxamate (NAH), N -methyl nicotinic acid hydroxamate (NAH-M), and kojic acid, were studied. The tyrosinase inhibitory activity was found to follow the trend: NAH > kojic acid > NAH-M > methyl nicotinate > nicotinamide. The concentrations of half-inhibition (IC 50 ) of NAH against monophenolase and diphenolase activity were 2 and 1 μM, respectively; the inhibition mode was a mixed-type in the former and an uncompetitive type in the latter. In the antioxidant activity assays, NAH and NAH-M, but not nicotinamide or methyl nicotinate, showed dose-dependent DPPH radical scavenging activity, and their corresponding IC 50 values were 65.81 and 125 μM, respectively. NAH and NAH-M also showed hydroxyl radical scavenging activity and anti-low-density-lipoprotein peroxidation. These results indicate that NAH and NAH-M have the potential to be useful in cosmetics or food processing, and therefore, they should be investigated further.

Osteoporosis is a reduction in skeletal mass due to an imbalance between bone resorption and bone formation. Bone morphogenetic protein (BMP) plays important roles in osteoblastic differentiation and bone formation. Therefore, components involved in BMP activation are good targets for the development of anti-osteoporosis drugs. In this study, imperatorin and bergapten, two coumarin derivatives, were shown to enhance alkaline phosphatase (ALP) activity, type I collagen synthesis and bone nodule formation in primary cultured osteoblasts. Imperatorin and bergapten increased mRNA levels of BMP-2 using quantitative RT-PCR, whereas the BMP-2 antagonist noggin attenuated the increase of ALP activity induced by imperatorin and bergapten, indicating that BMP-2 expression is required for the action of imperatorin and bergapten in osteoblastic maturation. Both imperatorin and bergapten enhanced the phosphorylation of SMAD (transcription factors activated by TGF-beta) 1/5/8, p38 and extracellular signal-regulated protein (ERK). Pretreatment of osteoblasts with p38 inhibitor (SB203580) or mitogen-activated protein kinase inhibitor (PD98059) or transfected with dominant negative mutant of p38 or ERK antagonized the elevation of BMP-2 expression and ALP activity induced by imperatorin and bergapten. Local administration of imperatorin or bergapten into the metaphysis of the tibia via the implantation of a needle cannula significantly increased the BMP-2 immunostaining and bone volume of secondary spongiosa in tibia. Taken together, our results provide evidence that coumarin derivatives increase BMP-2 expression and enhance bone formation in rat via the p38 and ERK-dependent signaling pathway.