Dimethylarginine Dimethylaminohydrolase/Nitric Oxide Synthase Pathway in Liver and Kidney: Protective Effect of Cyanidin 3-O-β-D-Glucoside on Ochratoxin-A Toxicity
The aim of the present study was to evaluate the effect of long-term cyanidin 3-O-β-D-glucoside (C3G) and/or Ochratoxin A (OTA)-exposure on dimethylarginine dimethylamino hydrolase/nitric oxide synthase (DDAH/NOS) pathway in rats. The experiments were performed in rats supplemented with C3G (1 g/kg feed), OTA (200 ppb), and OTA + C3G. After 4 weeks of daily treatment, liver and kidneys were processed for eNOS, iNOS and DDAH-1 Western blotting, nitrite levels evaluation and DDAH activity determination. Results show that OTA is able to induce iNOS both in kidney and liver, whereas OTA is able to induce eNOS and DDAH-1 overexpression and DDAH activation only in kidney, resulting in increased nitrite levels. In kidney of OTA + C3G fed rats, iNOS, eNOS and DDAH-1 expression were less pronounced compared with those observed in the OTA-treated group. Coherent with the decreased iNOS, eNOS and DDAH-1 expression a decrease in nitrite levels and DDAH activity was observed in the OTA + C3G group. Results demonstrate that C3G is able to counteract the deleterious effects of chronic consumption of OTA and also suggest a possible involvement of iNOS-eNOS-DDAH impairment in OTA nephrocarcinogenity.
References
[1]
Clark, H.A.; Snedeker, S.M. Ochratoxin A: Its cancer risk and potential for exposure. J. Toxicol. Environ. Health B Crit. Rev. 2006, 9, 265–296.
[2]
J？rgensen, K.; Rasmussen, G.; Thorup, I. Ochratoxin A in Danish cereals 1986–1992 and daily intake by the Danish population. Food Addit. Contam. 1996, 13, 95–104.
[3]
Pitt, J.I. Penicillium viridicatum, Penicillium verrucosum, and production of ochratoxin A. Appl. Environ. Microbiol. 1987, 53, 266–269.
[4]
Pfohl-Leszkowicz, A.; Manderville, R.A. Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans. Mol. Nutr. Food Res. 2007, 51, 61–99.
[5]
Vrabcheva, T.; Petkova-Bocharova, T.; Grosso, F.; Nikolov, I.; Chernozemsky, I.N.; Castegnaro, M.; Dragacci, S. Analysis of ochratoxin A in foods consumed by in habitants from an area with balkan endemic nephropathy: A 1 month follow-up study. J. Agric. Food Chem. 2004, 52, 2404–2410.
[6]
Cavin, C.; Delatour, T.; Marin-Kuan, M.; Holzhauser, D.; Higgins, L.; Bezencon, C.; Guignard, G.; Junod, S.; Richoz-Payot, J.; Gremaud, E.; Hayes, J.D.; Nestler, S.; Mantle, P.; Schilter, B. Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. Toxicol. Sci. 2007, 96, 30–39.
[7]
Di Giacomo, C.; Acquaviva, R.; Piva, A.; Sorrenti, V.; Vanella, L.; Piva, G.; Casadei, G.; La Fauci, L.; Ritieni, A.; Bognanno, M.; di Renzo, L.; Barcellona, M.L.; Morlacchini, M.; Galvano, F. Protective effect of cyanidin 3-O-β-D-glucoside on ochratoxin A-mediated damage in the rat. Brit. J. Nutr. 2007, 98, 937–943.
[8]
Cavin, C.; Delatour, T.; Marin-Kuan, M.; Fenaille, F.; Holzhauser, D.; Guignard, G.; Bezencxon, C.; Piguet, D.; Parisod, V.; Richoz-Payot, J.; Schilter, B. Ochratoxin A-Mediated DNA and protein damage: Roles of nitrosative and oxidative stresses. Toxicol. Sci. 2009, 11, 84–94.
[9]
Chinje, E.C.; Stratford, I.J. Role of nitric oxide in growth of solid tumours: a balancing act. Essays Biochem. 1997, 32, 61–72.
[10]
Griffioen, A.W.; Molema, G. Angiogenesis: potentials or pharmacologic intervention in the treatment of cancer; cardiovascular diseas and crhonic inflammation. Pharm. Rev. 2000, 52, 237–268.
[11]
Chen, G.G.; Lee, T.W.; Xu, H.; Yip, J.H.; Li, M.; Mok, T.S.; Yim, A.P. Increased inducible nitric oxide synthase in lung carcinoma of smokers. Cancer 2008, 112, 372–381.
[12]
Lukes, P.; Pàcovà, H.; Kucera, T.; Vesely, D.; Martinek, J.; Asti, J. Expression of endothelial and inducible nitric oxide synthase and caspase-3 in tonsillar cancer; chronic tonsillitis and healthy tonsils. Folia Biol. 2008, 5, 141–145.
[13]
Brennan, P.A.; Palacios-Callender, M.; Zaki, G.A.; Spedding, A.V.; Langdon, J.D. Type II nitric oxide synthase (NOS2) expression correlates with lynphnode status in oral squamous carcinoma. J. Oral Pathol. Med. 2001, 30, 129–134.
[14]
Lim, K.H.; Ancrile, B.B.; Kashatus, D.F.; Counter, C.M. Tumour maintenance is mediated by eNOS. Nature 2008, 452, 646–649.
[15]
Shang, Z.J.; Li, J.R. Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in oral squamous cell carcinoma: its correlation with angiogenesis and disease progression. J. Oral Pathol. Med. 2005, 34, 134–139.
[16]
Kostourou, V.; Robinson, S.P.; Cartwright, J.E.; Whitley, G.S. Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis. Br. J. Cancer 2002, 87, 673–680.
[17]
Leiper, J.; Santa Maria, J.; Chubb, A.; MacAllister, R.J.; Charles, I.G.; Whithley, G.S.J.; Vallance, P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology to microbial arginine deiminases. Biochem. J. 1999, 343, 209–214.
[18]
Nijveldt, R.J.; Teerlink, T.; van Guldener, C.; Prins, H.A.; van Lambalgen, A.A.; Stehouwer, C.D.; Rauwerda, J.A.; van Leeuwen, P.A. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol. Dial. Transplant. 2003, 18, 2542–2550.
[19]
Tran, C.T.; Fox, M.F.; Vallance, P.; Leiper, J.M. Chromosomal localization; gene structure; and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics 2000, 68, 101–105.
[20]
Russo, A.; la Fauci, L.; Acquaviva, R.; Campisi, A.; Raciti, G.; Scifo, C.; Renis, M.; Galvano, G.; Vanella, A.; Galvano, F. Ochratoxin A-induced DNA damage in human fibroblast: Protective effect of cyanidin 3-O-β-D-glucoside. J. Nutr. Biochem. 2005, 16, 31–37.
[21]
Acquaviva, R.; Campisi, A.; Murabito, P.; Raciti, G.; Avola, R.; Mangiameli, S.; Musumeci, I.; Barcellona, M.L.; Vanella, A.; Li Volti, G. Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: An alternative protective mechanism. Anesthesiology 2004, 101, 1363–1371.
[22]
Lowry, O.H.; Rosenbrough, N.J.; Farr, A.J.; Randall, R.G. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951, 193, 265–275.
[23]
Knipp, M.; Vasak, M. A colorimetric 96-well microtirer plate assay for the determination of enzymatically formed citrulline. Anal. Biochem. 2000, 286, 257–264.
[24]
Grusak, M.A. Phytochemicals in plants: genomics-assisted plant improvement for nutritional and health benefits. Curr. Opin. Biotechnol. 2002, 13, 508–511.
[25]
Palombo, E.A. Phytochemicals from traditional medicinal plants used in the treatment of diarrhoea: modes of action and effects on intestinal function. Phytother. Res. 2006, 20, 717–724.
[26]
Talalay, P.; Fahey, J.W. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J. Nutr. 2001, 131, 3027S–3033S.
[27]
Noda, Y.; Kaneyuki, T.; Mori, A.; Packer, L. Antioxidant activities of pomegranate fruit extract and its anthocyanidins: delphinidin; cyanidin; and pelargonidin. J. Agric. Food Chem. 2002, 50, 166–171, doi:10.1021/jf0108765.
[28]
Seeram, N.P.; Momin, R.A.; Nair, M.G.; Bourquin, L.D. Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries. Phytomedcine 2001, 8, 362–369.
[29]
Amorini, A.M.; Lazzarino, G.; Galvano, F.; Fazzina, G.; Tavazzi, B.; Galvano, G. Cyanidin-3-O-beta-glucopyranoside protects myocardium and erythrocytes from oxygen radical-mediated damages. Free Radic. Res. 2003, 37, 453–460.
[30]
Serraino, I.; Dugo, L.; Dugo, P.; Mondello, L.; Mazzon, E.; Dugo, G.; Caputi, A.P.; Cuzzocrea, S. Protective effects of cyanidin-3-O-glucoside from blackberry extract against peroxynitrite- induced endothelial dysfunction and vascular failure. Life Sci. 2003, 73, 1097–1114.
[31]
Ding, M.; Feng, R.; Wang, S.Y.; Bowman, L.; Lu, Y.; Qian, Y.; Castranova, V.; Jiang, B.H.; Shi, X. Cyanidin-3-glucoside; a natural product derived from blackberry; exhibits chemopreventive and chemotherapeutic activity. J. Biol. Chem. 2006, 281, 17359–17668.
[32]
World Health Organization (WHO). Evaluation of certain food additives and contaminants. In Proceedings of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), Geneva, Switzerland, 19–28 June 2007; 947, pp. 169–180. WHO Food Additives Series 44.
[33]
Arbillaga, L.; Azqueta, A.; van Delft, J.H.; Lopez de Cerain, A. In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol. Appl. Pharmacol. 2007, 220, 216–224.
[34]
Pfohl-Leszkowicz, A.; Manderville, R.A. An update on direct genotoxicity as a molecular mechanism of ochratoxin a carcinogenicity. Chem. Res. Toxicol. 2012, 25, 252–262.
[35]
Fusi, E.; Rebucci, R.; Pecorini, C.; Campagnoli, A.; Pinotti, L.; Saccone, F.; Cheli, F.; Purup, S.; Sejrsen, K.; Baldi, A. Alpha-tocopherol counteracts the cytotoxicity induced by ochratoxin a in primary porcine fibroblasts. Toxins 2010, 2, 1265–1278.
[36]
Manderville, R.A. A case for the genotoxicity of ochratoxin a by bioactivation and covalent DNA adduction. Chem. Res. Toxicol. 2005, 18, 1091–1097.
[37]
European Food Safety Authority (EFSA). Opinion of the scientific panel on contaminants in the food chain on a request from the commission related to ochratoxin A in food. EFSA J. 2006, 365, 1–56.
[38]
Petrik, J.; Zanic-Grubisic, T.; Barisic, K.; Pepeljnjak, S.; Radic, B.; Ferencic, Z.; Cepelak, I. Apoptosis and oxidative stress induced by ochratoxin-A in rat kidney. Arch. Toxicol. 2003, 77, 685–693.
[39]
Gekle, M.; Sauvant, C.; Schwerdt, G. Ochratoxin A at nanomolar concentrations: A signal modulator in renal cells. Mol. Nutr. Food Res. 2005, 49, 118–130.
[40]
Gagliano, N.; Doone, I.D.; Torri, C.; Migliori, M.; Grizzi, F.; Milzani, A.; Filippi, C.; Annoni, G.; Colombo, P.; Costa, F.; Ceva-Grimaldi, G.; Bertelli, A.A.; Giovannini, L.; Gioia, M. Early cytotoxic effects of ochratoxin A in rat liver: A morphological, biochemical and molecular study. Toxicology 2006, 225, 214–224.
[41]
Vettorazzi, A.; de Trocóniz, I.F.; González-Pe？as, E.; Arbillaga, L.; Corcuera, L.A.; Gil, A.G.; de Cerain, A.L. Kidney and liver distribution of ochratoxin A in male and female F344 rats. Food Chem. Toxicol. 2011, 49, 1935–1942.
[42]
Ferrante, M.C.; Mattace Raso, G.; Bilancione, M.; Esposito, E.; Iacono, A.; Meli, R. Differential modification of inflammatory enzymes in J774A.1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide. Toxicol. Lett. 2008, 181, 40–46, doi:10.1016/j.toxlet.2008.06.866.
[43]
Radi, R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc. Natl. Acad. Sci. USA 2004, 101, 4003–4008.
[44]
Wang, Q.; Xia, M.; Liu, C.; Guo, H.; Ye, Q.; Hu, Y.; Zhang, Y.; Hou, M.; Zhu, H.; Ma, J.; Ling, W. Cyanidin-3-O-β-glucoside inhibits iNOS and COX-2 expression by inducing liver X receptor alpha activation in THP-1 macrophages. Life Sci. 2008, 83, 176–184.
