NOBILETIN TRANSIENTLY INCREASES THE PRODUCTION OF NITRIC OXIDE AND CHANGES THE ACTIVITY OF SUCCINATE DEHYDROGENASE IN HUMAN BLOOD LYMPHOCYTES

Abstract

The citrus flavonoids exhibit abilities to modulate the inflammatory response and carcinogenesis via several different mechanisms. We have studied the effects of two major citrus flavonoids – nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone), and sinensetin (5,6,7,3′,4′-pentamethoxyflavone) on the spontaneous synthesis of nitric oxide (NO), succinate dehydrogenase (SDH) activity and the copper redox state of cytochrome c oxidase in human peripheral blood lymphocytes. Our results showed that in contrast to sinensetin, nobiletin causes a transient enhancement in the production of NO, which leads to a subsequent compensatory elevation of cytochrome c oxidase and SDH. High positive correlation between NO production and level of oxidation of copper in cytochrome oxidase and inverse correlation with the activity of SDH were found. We propose that temporal alterations of mitochondrial enzymes could mediate immunomodulatory and anticarcinogenic effects of nobiletin. PRACTICAL APPLICATIONS Positive correlation between nitric oxide production and level of oxidation of copper in cytochrome oxidase and inverse correlation with the activity of succinate dehydrogenase (SDH) were found in peripheral blood lymphocytes after treatment of cells by nobiletin. These results demonstrate that the beneficial immunomodulatory and anticarcinogenic effects of nobiletin possibly involve the transient inhibition of mitochondrial respiratory chain and subsequent compensatory elevation of SDH activity. Our findings indicate new steps in the molecular mechanism of nobiletin effects, suggesting new potential pharmacological actions of nutritional citrus flavonoids.