Suppression of Inducible Nitric Oxide Production by Indole and Isothiocyanate Derivatives from Brassica Plants in Stimulated Macrophages

Abstract

In this study, the effects of bioactive compounds derived from vegetables of the Brassica genus (Brassicaceae) including 2-phenylethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), and indolo[3,2-b]carbazole (ICZ), on the inhibition of NO production in RAW 264.7 cells were explored. The results indicated that PEITC and I3C inhibited lipopolysaccharide (LPS)- and interferon-γ (IFN-γ)-induced NO production in RAW 264.7 cells, and this inhibition was in accordance with lowering the expression of iNOS protein and mRNA. On the contrary, ICZ, a derivative of I3C, had no significant effect on the stimulated NO production. In conclusion, the Brassica plants derivatives, PEITC and, to a lesser extent, I3C inhibit the LPS/IFN-γ-induced NO production by lowering iNOS protein and mRNA expression in RAW 264.7 cells, in which the PEITC had a more potent inhibitory effect. Nevertheless, ICZ exhibits no inhibitory effect on the activated NO production (Indole-3-carbinol = indole-3-methanol).

Key words

Brassicaceae - indole - isothiocyanate - nitric oxide - inducible nitric oxide synthase - RAW 264.7 macrophages

References

• 1 Davis K L, Martin E, Turko I V, Murad F. Novel effects of nitric oxide.  Annu Rev Pharmacol Toxicol. 2001;  41 203-36
• 2 Kroncke K D, Fehsel K, Kolb-Bachofen V. Inducible nitric oxide synthase in human diseases.  Clin Exp Immunol. 1998;  113 147-56
• 3 Tamir S, Tannenbaum S R. The role of nitric oxide (NO) in the carcinogenic process.  Biochim Biophys Acta. 1996;  1288 F31-6
• 4 Graham S, Mettlin C. Diet and colon cancer.  Am J Epidemiol. 1979;  109 1-20
• 5 Stoewsand G S. Bioactive organosulfur phytochemicals in Brassica oleracea vegetables - a review.  Food Chem Toxicol. 1995;  33 537-43
• 6 McDanell R, McLean A EM, Hanley A B, Heaney R K, Fenwick G R. Chemical and biological properties of indole glucosinolates (glucobrassicins): a review.  Food Chem Toxicol. 1988;  26 59-70
• 7 Kwon C -S, Grose K R, Riby J, Chen Y -H, Bjeldanes L F. In vivo production and enzyme-inducing activity of indolo[3,2-b]carbazole.  J Agric Food Chem. 1994;  42 2536-40
• 8 Zhang Y, Talalay P. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms.  Cancer Res. 1994;  54(suppl) 1976S-81S
• 9 Robinson B. The Fischer indolisation of cyclohexane-1,4-dione bisphenylhydrazone. J Chem Soc 1963: 3097-9
• 10 Privat C, Lantoine F, Bdeioui F, van Brussel E M, Devynck J, Devynck M A. Nitric oxide production by endothelial cells: comparison of three methods of quantification.  Life Sci. 1997;  61 1193-202
• 11 Noda T, Amano F. Differences in nitric oxide synthase activity in a macrophage-like cell line, RAW 264.7 cells, treated with lipopolysaccharide (LPS) in the presence or absence of interferon-γ (IFN-γ): possible heterogeneity of iNOS activity.  J Biochem. 1997;  121 38-46
• 12 Tsai S H, Lin-Shiau S Y, Lin J K. Suppression of nitric oxide synthase and the down-regulation of the activation of NFκB in macrophages by resveratrol.  Brit J Pharmacol. 1999;  126 673-80
• 13 Bradfield C A, Bjeldanes L F. Effect of dietary indole-3-carbinol on intestinal and hepatic monooxygenase, glutathione S-transferase and epoxide hydrolase activities in the rat.  Food Chem Toxicol. 1984;  22 977-82
• 14 Guo Z, Smith T J, Wang E, Sadrieh N, Ma Q, Thomas P E. et al . Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats.  Carcinogenesis. 1992;  13 2205-10
• 15 Bonnesen C, Eggleston I M, Hayes J D. Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines.  Cancer Res. 2001;  61 6120-30
• 16 Ge X, Fares F A, Yannai S. Induction of apoptosis in MCF-7 cells by indole-3-carbinol is independent of p53 and Bax.  Anticancer Res. 1999;  19 3199-204
• 17 Ohshima H, Bartsch H. Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis.  Mutation Res. 1994;  305 253-64
• 18 Grose K R, Bjeldanes L F. Oligomerization of indole-3-carbinol in aqueous acid.  Chem Res Toxicol. 1992;  5 188-93
• 19 Bjeldanes L F, Kim J -Y, Grose K R, Bartholomew J C, Bradfield C A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.  Proc Natl Acad Sci USA. 1991;  88 9543-7
• 20 Liu H, Wormke M, Safe S H, Bjeldanes L F. Indolo[3,2-b]carbazole: a dietary-derived factor that exhibits both antiestrogenic and estrogenic activity.  J Natl Cancer Inst. 1994;  86 1758-65