IN-VIVO INHIBITION OF NITRIC-OXIDE SYNTHASE GENE-EXPRESSION BY CURCUMIN, A CANCER PREVENTIVE NATURAL PRODUCT WITH ANTIINFLAMMATORY 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-inf lammation. With respect to inflammation, in vitro, it inhibits the act ivation of free radical activated transcription factors, such as nucle ar factor kappa B (NF kappa B) and AP-1, and reduces the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF al pha), interleukin-1 beta (IL-1 beta), and interleukin-8. Inducible nit ric oxide synthase (iNOS) is an inflammation induced enzyme that catal yzes 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 o f iNOS mRNA in a concentration-dependent manner. Furthermore, we demon strated that, in vivo, two oral treatments of 0.5 mt of a 10-mu M solu tion of curcumin (92 ng/g of body weight) reduced iNOS mRNA expression in the livers of lipopolysaccharide (LPS)-injected mice by 50-70%. Al though many hold that curcumin needs to be given at dosages that are u nattainable 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 regi men: 1) an aqueous solution of curcumin was prepared by initially diss olving 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 w as not observed in mice that were fed ad lib., suggesting that food in take may interfere with the absorption of curcumin. BIOCHEM PHARMACOL 55;12:1955-1962, 1998. (C) 1998 Elsevier Science Inc.