Effects of Lycopene, Indole-3-Carbinol, and Luteolin on Nitric Oxide Production and iNOS Expression are Organ-Specific in Rats

Open access

Effects of Lycopene, Indole-3-Carbinol, and Luteolin on Nitric Oxide Production and iNOS Expression are Organ-Specific in Rats

Natural compounds are known to modify NO content in tissues; however, the biological activity of polyphenol-rich food often does not correspond to the effects of individual polyphenols on NO synthase activity. The aim of this study was to see how natural compounds luteolin, indole-3-carbinol, and lycopene modify NO production in rat tissues and change the expression of the iNOS gene and protein. Indole-3-carbinol produced multiple effects on the NO level; it significantly decreased NO concentration in blood, lungs, and skeletal muscles and increased it in the liver. Indole-3-carbinol enhanced lipopolyssaccharide (LPS)-induced NO production in all rat organs. It decreased iNOS gene expression in the brain cortex of animals that did not receive LPS and up-regulated it in the LPS-treated animals. Lycopene increased the iNOS gene transcription rate in the brain cortex of LPS-treated animals. Luteolin did not modify NO production in any organ of LPS-untreated rats, nor did it affect gene expression in the liver. In the brain it slightly decreased iNOS gene expression. Luteolin decreased NO production in the blood of LPS-treated animals and the number of iNOS-positive cells in these animals. Our results suggest that changes in tissue NO levels caused by natural compounds cannot be predicted from their effect on NOS expression or activity obtained in model systems. This stresses the importance of direct measurements of NO and NOS expression in animal tissues.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Ferguson LR. Role of plant polyphenols in genomic stability. Mutat Res 2001;475:89-111.

  • Sarkar FH Li Y Wang Z Kong D. Cellular signalling perturbation by natural products. Cell Signal 2009;21:154-7.

  • Olszanecki R Gebska A Kozlovski VI Gryglewski RJ. Flavonoids and nitric oxide synthase. J Physiol Pharmacol 2002;53:571-84.

  • Benito S Lopey D Sáiz MP Buxaderas S Sánchez J Puig-Parellada P Mitjavila MT. A flavonoid-rich diet increases nitric oxide production in rat aorta. Br J Pharmacol 2002;135:910-6.

  • Kim BH Cho SM Reddy AM Kim YS Min KR Kim Y. Down-regulatory effect of quercitrin gallate on nuclear factor-kappa B-dependent inducible nitric oxide synthase expression in lipopolysaccharide-stimulated macrophages RAW 264.7. Biochem Pharmacol 2005;69:1577-83.

  • Wallerath T Li H Gödtel-Ambrust U Schwarz PM Förstermann U. A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 2005;12:97-104.

  • Luo L Sun Q Mao YY Lu YH Tan RX. Inhibitory effects of flavonoids from Hypericum perforatum on nitric oxide synthase. J Ethnopharmacol 2004;93:221-5.

  • Chen CK Pace-Asciak CR. Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol 1996;27:363-6.

  • Stoclet JC Kleschyov A Andriambeloson E Diebolt M Andriantsitohaina R. Endothelial NO release caused by red wine polyphenols. J Physiol Pharmacol 1999;50:535-40.

  • Shutenko YZ Henry Y Pinard E Seylaz J Potier P Berthet F Girard P Sercombe R. Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Biochem Pharmacol 1999;57:199-208.

  • van Meeteren ME Hendriks JJ Dijkstra CD van Tol EA. Dietary compounds prevent oxidative damage and nitric oxide production by cells involved in demyelinating disease. Biochem Pharmacol 2004;67:967-75.

  • Rahman KM Ali S Aboukameel A Sarkar SH Wang Z Philip PA Sakr WA Raz A. Inactivation of NF-kappaB by 33'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells. Mol Cancer Ther 2007;6:2757-65.

  • Panasenko OM Sharov VS Briviba K Sies H. Interaction of peroxynitrite with carotenoids in human low density lipoproteins. Arch Biochem Biophys 2000;373:302-5.

  • Kim SJ Park H Kim HP. Inhibition of nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells by synthetic flavones: structure-activity relationship and action mechanism. Arch Pharm Res 2004;27:937-43.

  • Kim JS Lee HJ Lee MH Kim J Jin C Ryu JH. Luteolin inhibits LPS-stimulated inducible nitric oxide synthase expression in BV-2 microglial cells. Planta Med 2006;72:65-8.

  • Hu C Kitts DD. Luteolin and luteolin-7-O-glucoside from dandelion flower suppress iNOS and COX-2 in RAW264.7 cells. Mol Cell Biochem 2004;265:107-13.

  • Scuro LS Simioni PU Grabriel DR Saviani EE Modolo LV Tamashiro WM Salgado I. Suppression of nitric oxide production in mouse macrophages by soybean flavonoids accumulated in response to nitroprusside and fungal elicitation. BMC Biochem 2004;5:5.

  • Li H Xia N Brausch I Yao Y Förstermann U. Flavonoids from artichoke (Cynara scolymus L.) up-regulate endothelialtype nitric-oxide synthase gene expression in human endothelial cells. J Pharmacol Exp Ther 2004;310:926-32.

  • Gerhäuser C Klimo K Heiss E Neumann I Gamal-Eldeen A Knauft J Liu GY Sitthimonchai S Frank N. Mechanism-based in vitro screening of potential cancer chemopreventive agents. Mutat Res 2003;523-524:163-72.

  • Directive 86/609/EEC "European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes" ECBR European Coalition for Biomedical Research http://www.ecbr.eu/directive86609_2.htm

  • Kleschyov AL Wenzel P Münzel T. Electron paramagnetic resonance (EPR) spin trapping of biological nitric oxide. J Chromatogr B Analyt Technol Biomed Life Sci 2007;851:12-20.

  • Sjakste N Baumane L Meirena D Lauberte L Dzintare M Kalvinsh I. Drastic increase in nitric oxide content in rat brain under halothane anesthesia revealed by EPR method. Biochem Pharmacol 1999;58:1955-9.

  • Sjakste N Kleschyov AL Boucher JL Baumane L Dzintare M Meirena D Sjakste J Sydow K Münzel T Kalvinsh I. Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate. Eur J Pharmacol 2004;495:67-73.

  • Sjakste N Sjakste J Boucher JL Baumane L Sjakste T Dzintare M Meirena D Sharipova J Kalvinsh I. Putative role of nitric oxide synthase isoforms in the changes of nitric oxide concentration in rat brain cortex and cerebellum following sevoflurane and isoflurane anaesthesia. Eur J Pharmacol 2005;513:193-205.

  • Sjakste N Andrianov VG Boucher JL Shestakova I Baumane L Dzintare M Meirena D Kalvinsh I. Paradoxical effects of two oximes on nitric oxide production by purified NO synthases in cell culture and in animals. Nitric Oxide 2007;17:107-14.

  • Baumane L Dzintare M Zvejniece L Meirena D Lauberte L Sile V Kalvinsh I Sjakste N. Increased synthesis of nitric oxide in rat brain cortex due to halogenated volatile anesthetics confirmed by EPR spectroscopy. Acta Anaesthesiol Scand 2002;46:378-83.

  • Vandesompele J de Preter K Pattyn F Poppe B Van Roy N De Paepe A Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002;3: research0034.1-0034.11

  • Ishak K Baptista A Bianchi L Callea F De Groote J Gudat J Gudat F Denk H Desmet V Korb G MacSween RN. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-9.

  • Di Stefano A Caramori G Oates T Capelli A Lusuardi M Gnemmi I Ioli F Chung KF Donner CF Barnes PJ Adcock IM. Increased expression of nuclear factor-kB in bronchial biopsies from smokers and patients with COPD. Eur Respir J 2000;20:556-63.

  • Kim JS Jobin C. The flavonoid luteolin prevents lipopolysaccharide-induced NF-kappaB signalling and gene expression by blocking IkappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells. Immunology 2005;115:375-87.

  • Sies H Schewe T Heiss C Kelm M. Cocoa polyphenols and inflammatory mediators. Am J Clin Nutr 2005;81(Suppl 1):304S-12S.

  • Orallo F Alvarez E Camiña M Leiro JM Gómez E Fernández P. The possible implication of trans-Resveratrol in the cardioprotective effects of long-term moderate wine consumption. Mol Pharmacol 2002;61:294-302.

  • Rostoka E Baumane L Isajevs S Line A Dzintare M Svirina D Sharipova J Silina K Kalvinsh I Sjakste N. Effects of kaempferol and myricetin on inducible nitric oxide synthase expression and nitric oxide production in rats. Basic Clin Pharmacol Toxicol 2010;106:461-6.

  • Salerno JC Ghosh DK. Space time and nitric oxide - neuronal nitric oxide synthase generates signal pulses. FEBS J 2009;276:6677-88.

Search
Journal information
Impact Factor

IMPACT FACTOR 2018: 1.436
5-year IMPACT FACTOR: 1.606

CiteScore 2018: 1.53

SCImago Journal Rank (SJR) 2018: 0.358
Source Normalized Impact per Paper (SNIP) 2018: 0.608

Cited By
Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 283 191 8
PDF Downloads 117 90 7