PENTAMETHYL-HYDROXYCHROMANE, VITAMIN-E DERIVATIVE, INHIBITS INDUCTIONOF NITRIC-OXIDE SYNTHASE BY BACTERIAL LIPOPOLYSACCHARIDE

Vitamin E, a lipophilic antioxidant, has effectively inhibited the act ivation of cytokine-induced nuclear factor kB (NFkB). Since NFkB plays a critical role in the induction of an isoform of nitric oxide syntha se (iNOS) gene by lipopolysaccharide (LPS), we investigated the effect of a vitamin E derivative, pentamethyl-hydroxychromane (PMC), which i s an extremely potent inhibitor of NFkB activation, on the induction o f nitric oxide (NO) synthesis and iNOS mRNA by LPS. PMC inhibited the LPS-stimulated induction of NO production in a concentration-dependent fashion in cultured J774 macrophages and rat vascular smooth muscle c ells without evidence of cytotoxicity. However, the addition of PMC to J774 macrophages after the induction of iNOS did not inhibit NO produ ction. Treatment of J774 macrophages with LPS resulted in a significan t expression of iNOS mRNA, which was profoundly reduced by PMC. Data s uggest that PMC inhibits the induction of iNOS by preventing iNOS gene expression through inhibition of NFkB activation.