In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer preventive drug development and whose working pharmacological actions include anti-inflammation. With respect to inflammation, in vitro, it inhibits the activation of free radical activated transcription factors, such as nuclear factor kappa B (NF kappa B) and AP-1, and reduces the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and interleukin-8. Inducible nitric oxide synthase (iNOS) is an inflammation induced enzyme that catalyzes the production of nitric oxide (NO), a molecule that may lead to carcinogenesis, Here, we report that in ex vivo cultured BALB/c mouse peritoneal macrophages, 1-20 mu M of curcumin reduced the production of iNOS mRNA in a concentration-dependent manner. Furthermore, we demonstrated that, in vivo, two oral treatments of 0.5 mt of a 10-mu M solution of curcumin (92 ng/g of body weight) reduced iNOS mRNA expression in the livers of lipopolysaccharide (LPS)-injected mice by 50-70%. Although many hold that curcumin needs to be given at dosages that are unattainable through diet to produce an in vivo effect, we were able to obtain potency at nanomoles per gram of body weight. This efficacy is associated with two modifications in our preparation and feeding regimen: 1) an aqueous solution of curcumin was prepared by initially dissolving the compound in 0.5 N NaOH and then immediately diluting it in PBS; and 2) mice were fed curcumin at dusk after fasting. Inhibition was not observed in mice that were fed ad lib., suggesting that food intake may interfere with the absorption of curcumin. BIOCHEM PHARMACOL 55;12:1955-1962, 1998. (C) 1998 Elsevier Science Inc.