Oral supplementation with troxerutin (trihydroxyethylrutin), modulates lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

doi:10.1016/j.etap.2013.11.022

Environmental Toxicology and Pharmacology

Volume 37, Issue 1, January 2014, Pages 174-184

https://doi.org/10.1016/j.etap.2013.11.022 Get rights and content

Highlights

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1,2-Dimethylhydrazine (DMH) is a colon-specific pro-carcinogen.
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Troxerutin acts as a free radical quencher.
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Troxerutin supplementation effectively modulates oxidative stress markers thereby playing a substantial role in growth inhibition.
•
Troxerutin more efficiently inhibited the formation of polyps and inflammatory response, which exerts chemopreventive effect of troxerutin.
•
Consumption of troxerutin in the diet could prevent early organ damage.

Abstract

The present study was aimed to investigate the chemopreventive potential of troxerutin on 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the antioxidant and lipid peroxidation (LPO) status. Rats were randomly divided into six groups. Group I rats served as control. Group II rats received troxerutin (50 mg/kg b.w., p.o.) for 16 weeks. Groups III–VI rats received subcutaneous injections of DMH (20 mg/kg b.w., s.c.) once a week, for the first 4 weeks. In addition to DMH, groups IV–VI rats received troxerutin at the doses of 12.5, 25 and 50 mg/kg b.w., respectively. In DMH treated rats, our results showed decreased activities of antioxidants and increased levels of LPO in the liver. Moreover, LPO and antioxidants in the colon were found to be significantly diminished in DMH the treated rats. Furthermore, enhanced activity of colonic vitamin C and vitamin E levels were observed in DMH alone treated rats (group III), which was significantly reversed on troxerutin supplementation. Troxerutin at the dose of 25 mg/kg b.w. had shown profound beneficial effects by exhibiting near normal biochemical profile and well-preserved colon histology as compared to the other two tested doses (12.5 and 50 mg/kg b.w.). These findings suggest that troxerutin could serve as a novel agent for colon cancer chemoprevention.

Introduction

Colon cancer is the third most common global oncologic problem faced by medical fraternity (Howe et al., 2006). It is still a leading cause of cancer death in the United States and is the fastest emerging gastrointestinal cancer in the Asia Pacific region (Siegel et al., 2011). Epidemiological studies have demonstrated that colon cancer development is closely associated with economic development, lifestyle and dietary habits. Particularly high fat and low carbohydrate diets have increased the risk of colon cancer incidence and mortality (Weisburger, 1991, Pisani et al., 2002, Johnson and Mukhtar, 2007).

1,2-Dimethylhydrazine (DMH) is a powerful colon specific carcinogen and it is being widely used to induce colon cancer in rodents (Heitman et al., 1983, Ohno et al., 2001). The cells at the subcutaneous site do not possess enzymes capable of reacting with DMH. Hence, subcutaneously injected DMH reaches the liver via circulation, and gets metabolized into various intermediates such as azoxymethane (AOM) and methylazoxymethanol (MAM) (Fiala, 1977, Oravec et al., 1986). Later on MAM is transported to the colon via bile or blood to generate its ultimate carcinogenic metabolite, electrophilic methyldiazonium ion, which inturn generates carbonium ion that is responsible for the methylation of nucleic acids that triggers colon carcinogenesis (Fiala, 1977, Taketo, 1998, Rosenberg et al., 2009).

The active metabolites of most carcinogens are thought to evoke the formation of oxygen-derived free radicals and intermediates of oxygen products such as hydrogen peroxides. Colon cancer is frequently a pathological consequence of persistent oxidative stress and inflammation (Bartsch and Nair, 2002, Terzic et al., 2010). It has also been reported that DMH produces free radicals that induce oxidative DNA damage in the liver and colon (No et al., 2007).

Natural products with diverse pharmacological properties are gaining more attention in the prevention and treatment of various diseases including cancer. Flavonoids are ubiquitous group of polyphenolic compounds obtained from edible fruits, vegetables and medicinal herbs, which could potentially prevent the development of cancer (Kelloff et al., 2000). Troxerutin (Fig. 1) a trihydroxyethylated derivative of the natural bioflavonoid rutin, known as vitamin P4, is a flavonoid present in tea, coffee, cereal grains, a variety of fruits and vegetables. Troxerutin has been commonly used in the treatment of chronic venous insufficiency (CVI). In addition it possesses broad pharmacological properties such as anti-thrombotic, fibrinolytic (Boisseau et al., 1995), odema-protective (Vanscheidt et al., 2002), antioxidant (Blasig et al., 1987), antiinflammatory (Fan et al., 2009), radio protective (Maurya et al., 2005) and antidiabetic (Chung et al., 2005) effects. Troxerutin has undergone numerous clinical trials in human subjects; even with high doses (4 or 7 g per day) it had an excellent safety and tolerability profile (Marhic, 1991, Wijayanegara et al., 1992, Glacet-Bernard et al., 1994). Till date no studies are available demonstrating the colon cancer chemopreventive efficacy of troxerutin using an in vivo model of colon cancer. This study provides the scientific evidence for the chemopreventive potential of troxerutin against DMH induced colon carcinogenesis by evaluating the effect of troxerutin on the status of lipid peroxidation and antioxidant profile in experimental rats.

Section snippets

Chemicals

Troxerutin and 1,2-dimethylhydrazine (DMH), were purchased from Sigma Chemicals Co., St. Louis, MO, USA. The rest of the chemicals and solvents utilized were of analytical grade and obtained from Hi-Media Laboratories Ltd., Mumbai, India.

Animals and diet

Male albino Wistar rats (5 weeks old) weighing 130–150 g were procured and maintained at the Central Animal House, Rajah Muthiah Medical College & Hospital, Annamalai University, Tamil Nadu, India. The rats were cared as per the principles and guidelines of the

Effect of troxerutin on body weight and growth rate changes

Growth rate was calculated as the difference between the final and initial body weight divided by the total number of days, i.e. 112 (Table 2). There was significant (P < 0.05) increase in the growth rate on troxerutin supplementation to DMH treated rats (groups IV, V and VI) as compared to unsupplemented DMH alone treated rats (group III). No significant changes were observed between control and control + troxerutin supplemented rats (group I and II). Among the different concentrations, troxerutin

Discussion

DMH induced rat colon carcinogenesis is a multistep process that involves stepwise accumulation of molecular and genetic defects in the colonic epithelial cells, i.e., changes in the normal epithelium, followed by hyperproliferation, that mimics human colon cancer (Perse and Cerar, 2011). Though all the rats in the experimental groups showed an increase in the body weight and growth rate throughout the study period, the decreased body weight and growth rate observed after 16 weeks in DMH alone

Conclusion

Overall the findings of the present study reveals that troxerutin supplementation attenuates DMH induced deleterious effects in the liver and colon of rats. This is the first scientific study exploring the chemopreventive potential of troxerutin against DMH induced rat colon carcinogenesis. Although 50 mg/kg b.w. of troxerutin was found to be beneficial, the medium dose of 25 mg/kg b.w. exhibited more pronounced effect as it constantly influenced all the biochemical parameters tested in this study.

Conflict of interest statement

The authors declared that there are no conflicts of interest.

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Dimethylhydrazine (DMH) is a potent colonic and hepatic carcinogen that is metabolized into oxyradicals causing liver injury and DNA mutations. Matricaria chamomilla is a well-documented medicinal herb that possesses anti-inflammatory, antioxidant and antitumor activities and is commonly used to treat diverse ailments. The present study aimed to reveal the hepatoprotective effects of Matricaria chamomilla aqueous extract during an intermediate stage of colorectal cancer (CRC) in mice. Male Balb/c mice were divided into six groups: group A served as control, group B received chamomile extract (150 mg/Kg b.w.) orally for 12 weeks, and groups C-F received weekly intraperitoneal injections of DMH (20 mg/Kg b.w.) once a week for 12 weeks. In addition to DMH, groups D and F received chamomile during the initiation and post-initiation stages, respectively. Blood and liver samples were collected for biochemical and molecular analyses. The results showed that DMH induced hepatic injury in mice as shown by significant increase in serum aspartate aminotransferase and alanine aminotransferase. The changes in biochemical parameters were accompanied by activation of the Wnt signaling pathway leading to increased hepatocytes proliferation as well as inflammation evidenced by high levels of pro-inflammatory enzymes cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). The results also showed potential hepatoprotective effects of chamomile extract against DMH-induced liver injury, proliferation and inflammation. Chamomile restored the biochemical and molecular parameters and this improvement was more pronounced in mice pretreated with the extract. In conclusion, chamomile extract may exert its hepatoprotective activities against DMH probably due to the antioxidant, antiproliferative and anti-inflammatory properties of its flavonoids.
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Furthermore, recent studies proposed TRX as a promising agent with neuroprotective effects on cognitive deficits [9], in Alzheimer’s disease [10] and in Parkinson’s disease [11]. Besides a number of other beneficial effects have been highlighted, such as the chemoprevention in colon carcinogenesis [12], hepatocellular carcinoma [13] and as adjuvant with 5-Fluorouracil in gastric cancer [14], a potential role against neuropathic pain [15], cardioprotective and antifibrogenic effects [16,17], its use as adjuvant in radiotherapy to protect normal tissues [18] and in the reduction of the severity of myocardial ischemia-reperfusion injury [19]. As a matter of fact, despite the lots of recent published in vitro and in vivo studies establishing new potential biological properties of this drug, TRX is always reported as triHer single isomer (3′,4′,7-tris(hydroxyethyl)rutin), without considering the presence, in the mixture, of the other Hers [20–23].
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Diabetes has various interactions with ischemic heart diseases. Troxerutin, a flavonoid, owns outstanding pharmacological potentials in cardiovascular medicine. The purpose of this study was to investigate the effects of troxerutin on phosphorylation of GSK-3β protein and apoptosis induced by myocardial ischemia–reperfusion injury in healthy and diabetic hearts. Male Wistar rats (n=36, 250–300 g) were randomly divided into four groups: healthy, diabetic, healthy-troxerutin and diabetic-troxerutin. Diabetes was induced by a single injection of streptozotocin (50 mg/kg; ip) and the diabetic period was lasted for ten weeks. Six weeks after induction of diabetes, troxerutin-treated groups received 150 mg/kg/day troxerutin by oral gavage for 4 weeks. The rats’ hearts were transferred to the Langendorff apparatus and then subjected to 30 min regional ischemia followed by 45 min reperfusion. Supernatants of the left ventricle were used to measure the levels of cardiac troponin-I (cTnI) by ELISA, total and phosphorylated form of GSK-3β by western blotting and tissue apoptosis by TUNEL assay. Troxerutin administration significantly decreased the cTnI levels in healthy and diabetic groups, as compared to the corresponding controls (P<0.05). In addition, troxerutin significantly increased the level of phosphorylated form and the ratio of phosphorylated to total form of GSK-3β in diabetic and control groups (P<0.05). Tissue apoptosis level and apoptotic index also showed a significant decrease after administration of troxerutin in control and diabetic groups (P<0.05). The findings indicated that the attenuation of GSK-3β activity and subsequent reduction of apoptosis by troxerutin play significant roles in its cardioprotection on reperfusion injuries.

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Oral supplementation with troxerutin (trihydroxyethylrutin), modulates lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

Highlights

Abstract

Introduction

Section snippets

Chemicals

Animals and diet

Effect of troxerutin on body weight and growth rate changes

Discussion

Conclusion

Conflict of interest statement

Biochim. Biophys. Acta

Cancer Detect. Prev.

Methods Enzymol.

Pharmacol. Res.

Arch. Biochem. Biophys.

Int. Immunopharmacol.

Am. J. Ophthalmol.

Cancer Lett.

J. Biol. Chem.

Anal. Biochem.

Cancer Lett.

J. Biol. Chem.

Med. Hypotheses

J. Biol. Chem.

Nutr. Res.

Free Radic. Biol. Med.

Anal. Biochem.

Phytomedicine

Cancer Lett.

J. Biol. Chem.

Cytokine Growth Factor Rev.

Hesperetin exerts dose dependent chemopreventive effect against 1,2-dimethylhydrazine induced rat colon carcinogenesis

Invest. New Drugs

Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose-dependent study

J. Pharm. Pharmacol.

Anticarcinogenic effects of the essential oils from cumin, poppy and basil

Phytoether. Res.

Plasma tocopherol in man at various times after ingesting free or acetylated tocopherol

Nutr. Rep. Int.

Effect of troxerutin and methionine on spin trapping of free oxy-radicals

Biomed. Biochim. Acta

Radical trapping and lipid peroxidation during myocardial reperfusion injury – radical scavenging by troxerutin in comparison to mannitol

Biomed. Biochem. Acta

Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind study of troxerutin efficiency

J. Cardiovasc. Surg.

Efficacy of troxerutin on streotozotocin induced rat model in the early stages of diabetic retinopathy

Arzneim. Forsch.

A radical approach to cancer

Med. Sci. Monit.

Systemic inflammation, cachexia and prognosis in patients with cancer

Curr. Opin. Clin. Nutr. Metab. Care

Free radical scavenger activity of rutosides

Minerva Cardioangiol.

Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane

Cancer

Chemopreventive efficacy of gallic acid, an antioxidant and anticarcinogenic polyphenol, against 1,2-dimethyl hydrazine induced rat colon carcinogenesis

Invest. New Drugs