Research Article
The evaluation of the therapeutic potential of hesperetin on diethylnitrosamine and phenobarbital induced liver injury in rats
Abstract
Nitrite and amine reactions can occur rapidly and produce nitrosamines, in-vivo. Diethylnitrosamine (DEN) and phenobarbital (PB) are readily inducing liver injury and hesperetin (HES), as a flavonoid found in citrus fruits, have the potential to compensate for their harmful effects. In this study, the therapeutic effects of HES were evaluated in DEN and PB mediated liver defect. Adult male Sprague-Dawley rats were split into 5 groups (n=10): Control, DEN, DEN+PB, HES, and DEN+PB+HES. 150 mg/kg DEN was applied intraperitoneally to DEN groups. Fifteen days after the DEN application 500ppm of PB was given in drinking water. HES were administered at 50 mg/kg dose orally for 8 weeks. Blood and liver malondialdehyde (MDA), glutathione (GSH) levels, and catalase (CAT), superoxide dismutase (SOD) activities were measured spectrophotometrically. Moreover, histologic examination of liver sections and apoptosis were determined with hematoxylin-eosin and TUNEL methods, respectively. DEN-PB application was found to increase blood and liver MDA levels and liver CAT activity, oppositely, decreased blood and liver SOD activity, GSH levels, and blood CAT activity. HES was found to have a positive impact on oxidative stress parameters by decreasing liver and blood MDA activity, increasing blood CAT and SOD activity together with liver GSH levels and SOD activity. Whereas DEN and PB application increased all histopathological findings and TUNEL positive cells, HES administration decreased these findings which might be important for the protection of liver cell structure from cell damage. These results suggest that HES administration could be an alternative therapeutic approach to liver damage.
Supporting Institution
This research was supported by a grant supplied from “Firat University Research Fund” (VF.16.22).
Project Number
VF.16.22
Thanks
This paper presented in International Conference on Multidisciplinary, Engineering, Science, Education and Technology, 2018, Dubai.
References
- Aebi H (1984): Catalase in vitro. Methods Enzymol, 105, 121–126.
- Alirezaei M, Kheradmand A, Heydari R, et al (2012): Oleuropein protects against ethanol-induced oxidative stress and modulates sperm quality in the rat testis. Med J Nutrition Metab, 5, 205–211.
- Aranganathan S, Nalini N (2009): Efficacy of the potential chemopreventive agent, hesperetin (citrus flavanone), on 1,2-dimethylhydrazine induced colon carcinogenesis. Food Chem Toxicol, 47, 2594–2600.
- Aranganathan S, Panneer Selvam J, Nalini N (2009): Hesperetin exerts dose dependent chemopreventive effect against 1,2-dimethyl hydrazine induced rat colon carcinogenesis. Invest New Drugs, 27, 203–213.
- Bai X, Yang P, Zhou Q, et al (2017): The protective effect of the natural compound hesperetin against fulminant hepatitis in vivo and in vitro. Br J Pharmacol, 174, 41–56.
- Banakar MC, Paramasivan SK, Chattopadhyay MB, et al (2004): 1α, 25-dihydroxyvitamin D3 prevents DNA damage and restores antioxidant enzymes in rat hepatocarcinogenesis induced by diethylnitrosamine and promoted by phenobarbital. World J Gastroenterol, 10, 1268–1275.
- Basaiawmoit SP, Alam A, Sohkhlet M, et al (2016): Diethylnitrosamine (DEN) induced morphological and biomolecular changes in mouse liver mitochondria. Indian J Biochem Biophys, 53, 187–198.
- Bennett CJ, Caldwell ST, McPhail DB, et al (2004): Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation. Bioorg Med Chem, 12, 2079–2098.
- Chavan S, Sava L, Saxena V, et al (2005): Reduced Glutathione: Importance of Specimen Collection. Indian J Clin Biochem, 20, 150–152.
- Choi EJ (2008): Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice. Life Sci, 82, 1059–1064.
- Drury R (1983): Theory and Practice of Histological Techniques. J Clin Pathol, 36, 609.
- Duran Y, Karaboğa İ (2020): Effect of hesperetin on systemic inflammation and hepatic injury after blunt chest trauma in rats. Biotech Histochem, 95, 297–304.
- El-Serag HB, Rudolph KL (2007): Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis. Gastroenterology, 132, 2557–2576.
- Erlund I (2004): Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res, 24, 851–874.
- Fathima MZ, Nainar M, Somasundaram I, et al (2018): Hinokitiol-ameliorated diethylnitrosamine-induced hepatocarcinogenesis through antioxidant mechanism in rats: In vitro and in vivo study. Asian J Pharm Clin Res, 11, 232–237.
- Ganeshpurkar A, Saluja AK (2017): The Pharmacological Potential of Rutin. Saudi Pharm J, 25, 149–164.
- Gokuladhas K, Jayakumar S, Rajan B, et al (2016): Exploring the Potential Role of Chemopreventive Agent, Hesperetin Conjugated Pegylated Gold Nanoparticles in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Male Wistar Albino Rats. Indian J Clin Biochem, 31, 171–184.
- Guzel EE, Kaya N, Ozan G, et al (2018): The investigation of effect of alpha lipoic acid against damage on neonatal rat lung to maternal tobacco smoke exposure. Toxicol Reports, 5, 714–722.
- Hussein UK, Mahmoud HM, Farrag AG, et al (2015): Chemoprevention of Diethylnitrosamine-Initiated and Phenobarbital-Promoted Hepatocarcinogenesis in Rats by Sulfated Polysaccharides and Aqueous Extract of Ulva lactuca. Integr Cancer Ther, 14, 525–545.
- Kakehashi A, Inoue M, Wei M, et al (2009): Cytokeratin 8 / 18 overexpression and complex formation as an indicator of GST-P positive foci transformation into hepatocellular carcinomas. Toxicol Appl Pharmacol, 238, 71–79.
- Karaca G, Sözbilir N (2007): Dietilnitrozamin Verilen Ratlarda Alfa Lipoik Asidin Koruyucu Etkilerinin Araştırılması. Kocatepe Tıp Derg, 7, 11–17.
- Kim JY, Jung KJ, Choi JS, et al (2004): Hesperetin: A potent antioxidant against peroxynitrite. Free Radic Res, 38, 761–769.
- Owumi SE, Dim UJ, Najophe ES (2019): Diethylnitrosamine aggravates cadmium-induced hepatorenal oxidative damage in prepubertal rats. Toxicol Ind Health, 35, 537–547.
- Parhiz H, Roohbakhsh A, Soltani F, et al (2015): Antioxidant and Anti-Inflammatory Properties of the Citrus Flavonoids Hesperidin and Hesperetin: An Updated Review of their Molecular Mechanisms and Experimental Models. Phyther Res, 29, 323–331.
- Pari L, Shagirtha K (2012): Hesperetin protects against oxidative stress related hepatic dysfunction by cadmium in rats. Exp Toxicol Pathol, 64, 513–520.
- Park J, Seo J, Lee J, et al (2015): Distribution of Seven N-Nitrosamines in Food. Toxicol Res, 31, 279–288.
- Paula Santos N, Colaço A, Gil da Costa RM, et al (2014): N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress. Exp Toxicol Pathol, 66, 429–436.
- Placer ZA, Cushman LL, Johnson BC (1966): Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem, 16, 359–364.
- Pradeep K, Mohan CVR, Gobianand K, et al (2007): Effect of Cassia fistula Linn. leaf extract on diethylnitrosamine induced hepatic injury in rats. Chem Biol Interact, 167, 12–18.
- Pradeep K, Mohan CVR, Gobianand K, et al (2007): Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol, 560, 110–116.
- Qintieri LQ, Bortolozzo S, Stragliotto S, et al (2010): Flavonoids Diosmetin and Hesperetin are Potent Inhibitors of Cytochrome P450 2C9-mediated Drug Metabolism in vitro. Drug Metab Pharmacokinet, 25, 466–476.
- Samie A, Sedaghat R, Baluchnejadmojarad T, et al (2018): Hesperetin, a citrus flavonoid, attenuates testicular damage in diabetic rats via inhibition of oxidative stress, inflammation, and apoptosis. Life Sci, 210, 132–139.
- Saraswati S, Alhaider AA, Agrawal SS (2013): Anticarcinogenic effect of brucine in diethylnitrosamine initiated and phenobarbital-promoted hepatocarcinogenesis in rats. Chem Biol Interact, 206, 214–221.
- Seifried HE, Anderson DE, Fisher EI, et al (2007): A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem, 18, 567–579.
- Shaban NZ, El-Kersh MAL, El-Rashidy FH, et al (2013): Protective role of Punica granatum (pomegranate) peel and seed oil extracts on diethylnitrosamine and phenobarbital-induced hepatic injury in male rats. Food Chem, 141, 1587–1596.
- Shang N, Bank T, Ding X, et al (2018): Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation. Cell Death Dis, 9, 558.
- Sherif IO (2018): The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway. Int Immunopharmacol, 61, 29–36.
- Spinardi-Barbisan ALT, Kaneno R, Marchesan Rodrigues MA, et al (2000): Lymphoproliferative response and T lymphocyte subsets in a medium-term multi-organ bioassay for carcinogenesis in Wistar rats. Cancer Lett, 154, 121–129.
- Sun Y, Oberley L, Li Y (1988): A Simple Method for ClinicalAssay of Superoxide Dismutase. Clin Chem, 34, 497–500.
- Vitaglione P, Morisco F, Caporaso N, et al (2005): Dietary Antioxidant Compounds and Liver Health. Crit Rev Food Sci Nutr, 44, 575–586.
- Wan J, Kuang G, Zhang L, et al (2020): Hesperetin attenuated acetaminophen-induced hepatotoxicity by inhibiting hepatocyte necrosis and apoptosis, oxidative stress and inflammatory response via upregulation of heme oxygenase-1 expression. Int Immunopharmacol, 83, 106435.
- Waris G, Ahsan H (2006): Reactive oxygen species: Role in the development of cancer and various chronic conditions. J Carcinog, 5, 1–8.
- Yadav AS, Bhatnagar D (2007): Chemo-preventive effect of Star anise in N-nitrosodiethylamine initiated and phenobarbital promoted hepato-carcinogenesis. Chem Biol Interact, 169, 207–214.
- Zhang J, Song J, Wu D, et al (2015): Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium. Med Oncol, 32, 1–11.
- Zhao X, Zhang JJ, Wang X, et al (2008): Effect of berberine on hepatocyte proliferation, inducible nitric oxide synthase expression, cytochrome P450 2E1 and 1A2 activities in diethylnitrosamine- and phenobarbital-treated rats. Biomed Pharmacother, 62, 567–572.
- Zhu C, Dong Y, Liu H, et al (2017): Hesperetin protects against H2O2-triggered oxidative damage via upregulation of the Keap1-Nrf2/HO-1 signal pathway in ARPE-19 cells. Biomed Pharmacother, 88, 124–133.
- Ziech D, Franco R, Georgakilas AG, et al (2010): The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development. Chem Biol Interact, 188, 334–339.
Year 2022,
, 149 - 156, 25.03.2022
Abstract
Project Number
VF.16.22
References
- Aebi H (1984): Catalase in vitro. Methods Enzymol, 105, 121–126.
- Alirezaei M, Kheradmand A, Heydari R, et al (2012): Oleuropein protects against ethanol-induced oxidative stress and modulates sperm quality in the rat testis. Med J Nutrition Metab, 5, 205–211.
- Aranganathan S, Nalini N (2009): Efficacy of the potential chemopreventive agent, hesperetin (citrus flavanone), on 1,2-dimethylhydrazine induced colon carcinogenesis. Food Chem Toxicol, 47, 2594–2600.
- Aranganathan S, Panneer Selvam J, Nalini N (2009): Hesperetin exerts dose dependent chemopreventive effect against 1,2-dimethyl hydrazine induced rat colon carcinogenesis. Invest New Drugs, 27, 203–213.
- Bai X, Yang P, Zhou Q, et al (2017): The protective effect of the natural compound hesperetin against fulminant hepatitis in vivo and in vitro. Br J Pharmacol, 174, 41–56.
- Banakar MC, Paramasivan SK, Chattopadhyay MB, et al (2004): 1α, 25-dihydroxyvitamin D3 prevents DNA damage and restores antioxidant enzymes in rat hepatocarcinogenesis induced by diethylnitrosamine and promoted by phenobarbital. World J Gastroenterol, 10, 1268–1275.
- Basaiawmoit SP, Alam A, Sohkhlet M, et al (2016): Diethylnitrosamine (DEN) induced morphological and biomolecular changes in mouse liver mitochondria. Indian J Biochem Biophys, 53, 187–198.
- Bennett CJ, Caldwell ST, McPhail DB, et al (2004): Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation. Bioorg Med Chem, 12, 2079–2098.
- Chavan S, Sava L, Saxena V, et al (2005): Reduced Glutathione: Importance of Specimen Collection. Indian J Clin Biochem, 20, 150–152.
- Choi EJ (2008): Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice. Life Sci, 82, 1059–1064.
- Drury R (1983): Theory and Practice of Histological Techniques. J Clin Pathol, 36, 609.
- Duran Y, Karaboğa İ (2020): Effect of hesperetin on systemic inflammation and hepatic injury after blunt chest trauma in rats. Biotech Histochem, 95, 297–304.
- El-Serag HB, Rudolph KL (2007): Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis. Gastroenterology, 132, 2557–2576.
- Erlund I (2004): Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res, 24, 851–874.
- Fathima MZ, Nainar M, Somasundaram I, et al (2018): Hinokitiol-ameliorated diethylnitrosamine-induced hepatocarcinogenesis through antioxidant mechanism in rats: In vitro and in vivo study. Asian J Pharm Clin Res, 11, 232–237.
- Ganeshpurkar A, Saluja AK (2017): The Pharmacological Potential of Rutin. Saudi Pharm J, 25, 149–164.
- Gokuladhas K, Jayakumar S, Rajan B, et al (2016): Exploring the Potential Role of Chemopreventive Agent, Hesperetin Conjugated Pegylated Gold Nanoparticles in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Male Wistar Albino Rats. Indian J Clin Biochem, 31, 171–184.
- Guzel EE, Kaya N, Ozan G, et al (2018): The investigation of effect of alpha lipoic acid against damage on neonatal rat lung to maternal tobacco smoke exposure. Toxicol Reports, 5, 714–722.
- Hussein UK, Mahmoud HM, Farrag AG, et al (2015): Chemoprevention of Diethylnitrosamine-Initiated and Phenobarbital-Promoted Hepatocarcinogenesis in Rats by Sulfated Polysaccharides and Aqueous Extract of Ulva lactuca. Integr Cancer Ther, 14, 525–545.
- Kakehashi A, Inoue M, Wei M, et al (2009): Cytokeratin 8 / 18 overexpression and complex formation as an indicator of GST-P positive foci transformation into hepatocellular carcinomas. Toxicol Appl Pharmacol, 238, 71–79.
- Karaca G, Sözbilir N (2007): Dietilnitrozamin Verilen Ratlarda Alfa Lipoik Asidin Koruyucu Etkilerinin Araştırılması. Kocatepe Tıp Derg, 7, 11–17.
- Kim JY, Jung KJ, Choi JS, et al (2004): Hesperetin: A potent antioxidant against peroxynitrite. Free Radic Res, 38, 761–769.
- Owumi SE, Dim UJ, Najophe ES (2019): Diethylnitrosamine aggravates cadmium-induced hepatorenal oxidative damage in prepubertal rats. Toxicol Ind Health, 35, 537–547.
- Parhiz H, Roohbakhsh A, Soltani F, et al (2015): Antioxidant and Anti-Inflammatory Properties of the Citrus Flavonoids Hesperidin and Hesperetin: An Updated Review of their Molecular Mechanisms and Experimental Models. Phyther Res, 29, 323–331.
- Pari L, Shagirtha K (2012): Hesperetin protects against oxidative stress related hepatic dysfunction by cadmium in rats. Exp Toxicol Pathol, 64, 513–520.
- Park J, Seo J, Lee J, et al (2015): Distribution of Seven N-Nitrosamines in Food. Toxicol Res, 31, 279–288.
- Paula Santos N, Colaço A, Gil da Costa RM, et al (2014): N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress. Exp Toxicol Pathol, 66, 429–436.
- Placer ZA, Cushman LL, Johnson BC (1966): Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem, 16, 359–364.
- Pradeep K, Mohan CVR, Gobianand K, et al (2007): Effect of Cassia fistula Linn. leaf extract on diethylnitrosamine induced hepatic injury in rats. Chem Biol Interact, 167, 12–18.
- Pradeep K, Mohan CVR, Gobianand K, et al (2007): Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol, 560, 110–116.
- Qintieri LQ, Bortolozzo S, Stragliotto S, et al (2010): Flavonoids Diosmetin and Hesperetin are Potent Inhibitors of Cytochrome P450 2C9-mediated Drug Metabolism in vitro. Drug Metab Pharmacokinet, 25, 466–476.
- Samie A, Sedaghat R, Baluchnejadmojarad T, et al (2018): Hesperetin, a citrus flavonoid, attenuates testicular damage in diabetic rats via inhibition of oxidative stress, inflammation, and apoptosis. Life Sci, 210, 132–139.
- Saraswati S, Alhaider AA, Agrawal SS (2013): Anticarcinogenic effect of brucine in diethylnitrosamine initiated and phenobarbital-promoted hepatocarcinogenesis in rats. Chem Biol Interact, 206, 214–221.
- Seifried HE, Anderson DE, Fisher EI, et al (2007): A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem, 18, 567–579.
- Shaban NZ, El-Kersh MAL, El-Rashidy FH, et al (2013): Protective role of Punica granatum (pomegranate) peel and seed oil extracts on diethylnitrosamine and phenobarbital-induced hepatic injury in male rats. Food Chem, 141, 1587–1596.
- Shang N, Bank T, Ding X, et al (2018): Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation. Cell Death Dis, 9, 558.
- Sherif IO (2018): The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway. Int Immunopharmacol, 61, 29–36.
- Spinardi-Barbisan ALT, Kaneno R, Marchesan Rodrigues MA, et al (2000): Lymphoproliferative response and T lymphocyte subsets in a medium-term multi-organ bioassay for carcinogenesis in Wistar rats. Cancer Lett, 154, 121–129.
- Sun Y, Oberley L, Li Y (1988): A Simple Method for ClinicalAssay of Superoxide Dismutase. Clin Chem, 34, 497–500.
- Vitaglione P, Morisco F, Caporaso N, et al (2005): Dietary Antioxidant Compounds and Liver Health. Crit Rev Food Sci Nutr, 44, 575–586.
- Wan J, Kuang G, Zhang L, et al (2020): Hesperetin attenuated acetaminophen-induced hepatotoxicity by inhibiting hepatocyte necrosis and apoptosis, oxidative stress and inflammatory response via upregulation of heme oxygenase-1 expression. Int Immunopharmacol, 83, 106435.
- Waris G, Ahsan H (2006): Reactive oxygen species: Role in the development of cancer and various chronic conditions. J Carcinog, 5, 1–8.
- Yadav AS, Bhatnagar D (2007): Chemo-preventive effect of Star anise in N-nitrosodiethylamine initiated and phenobarbital promoted hepato-carcinogenesis. Chem Biol Interact, 169, 207–214.
- Zhang J, Song J, Wu D, et al (2015): Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium. Med Oncol, 32, 1–11.
- Zhao X, Zhang JJ, Wang X, et al (2008): Effect of berberine on hepatocyte proliferation, inducible nitric oxide synthase expression, cytochrome P450 2E1 and 1A2 activities in diethylnitrosamine- and phenobarbital-treated rats. Biomed Pharmacother, 62, 567–572.
- Zhu C, Dong Y, Liu H, et al (2017): Hesperetin protects against H2O2-triggered oxidative damage via upregulation of the Keap1-Nrf2/HO-1 signal pathway in ARPE-19 cells. Biomed Pharmacother, 88, 124–133.
- Ziech D, Franco R, Georgakilas AG, et al (2010): The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development. Chem Biol Interact, 188, 334–339.
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Details
| Primary Language | English |
|---|---|
| Subjects | Veterinary Surgery |
| Journal Section | Research Article |
| Authors | |
| Project Number | VF.16.22 |
| Publication Date | March 25, 2022 |
| Published in Issue | Year 2022 |