Liver cancer is induced by a subnecrogenic dose of DENA when associated with fasting/refeeding: role of glutathione-transferase and lipid peroxidation

Muzio, Giuliana; Marengo, Barbara; Salvo, Raffaella A.; Semeraro, Antonella; Canuto, Rosa Angela; Tessitore, Luciana

doi:10.1016/s0891-5849(98)00329-3

Cited by 21 publications

(19 citation statements)

References 38 publications

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“…1,2 This intermediate can be metabolized by the phase II enzymes to a nontoxic compound or it can produce ethyl-diazonium ion, which directly ethylates cellular macromolecules. 10 Metabolic activation of NDEA by cytochrome P450 enzymes is responsible for its cytotoxic, mutagenic and carcinogenic effects. 22 Instrumental to them is the increased in ROS production caused by NDEA.…”

Section: Discussionmentioning

confidence: 99%

“…injection of NDEA at a dose of 200 mg/kg body weight in 1 ml saline followed by weekly s.c. injections of carbon tetrachloride for 6 weeks at individual doses of 3 ml/kg body weight. [10][11][12] Melatonin (5 mg/kg body weight) or its vehicle (0.5 ml of 5% ethanol in saline) was given i.p. daily 2 h before lights off for the whole experiment (20 weeks).…”

Section: Experimental Designmentioning

confidence: 99%

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24-Hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or α-ketoglutarate

et al. 2008

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To compare the effects of alpha-ketoglutarate (alpha-KG) and melatonin on 24-h rhythmicity of oxidative stress in N-nitrosodiethylamine (NDEA)-injected Wistar male rats, melatonin (5 mg/kg i.p.) or alpha-KG (2 g/kg through an intragastric tube) was given daily for 20 weeks. In blood collected at 6 time points during a 24-h period, serum activity of aspartate transaminase (AST) and alanine transaminase (ALT) and the levels of alpha-fetoprotein (alpha-FP) were measured as markers of liver function. To assess lipid peroxidation and the antioxidant status, plasma levels of thiobarbituric acid reactive substances (TBARS) and of reduced glutathione (GSH) were measured, together with the activity of erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST). NDEA augmented mesor and amplitude of rhythms in AST and ALT activity and plasma alpha-FP levels and mesor values of plasma TBARS, while decreasing mesor values of plasma GSH and erythrocyte SOD, CAT, GPx and GST. Acrophases were delayed by NDEA in all cases except for alpha-FP rhythm, which became phase-advanced. Co-administration of melatonin or alpha-KG partially counteracted the effects of NDEA. Melatonin decreased mesor of plasma TBARS and augmented mesor of SOD activity. The results indicate that melatonin and alpha-KG are effective in protecting from NDEA-induced perturbation of 24-h rhythms in oxidative stress. Melatonin augmented antioxidant defense in rats.

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

24-Hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or α-ketoglutarate

et al. 2008

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“…The metabolic activation of NDEA by cytochrome P450 enzymes converts it to ethyl-acetoxyethyl-nitrosamine, which can be conjugated by the phase II enzymes (Subramanian et al, 2007) to a non-toxic compound. Alternatively, it can form ethyldiazonium ion that directly ethylates cellular macromolecules (Muzio et al, 1999), and is responsible for its cytotoxic, mutagenic, and carcinogenic effects (Abdel-Hamid et al, 2013) through the production of ROS (Bansal et al, 2000). …”

Section: Introductionmentioning

confidence: 99%

Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress

et al. 2017

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Psychological stress contributes to increased susceptibility to a number of diseases including cancer. The present study was designed to assess the effect of chronic unpredictable stress on N-nitrosodiethylamine induced liver toxicity in terms of in vivo antioxidant status and DNA damage in Swiss albino mice. The animals used in this study were randomized into different groups based on the treatment with N-nitrosodiethylamine or chronic unpredictable stress alone and post-stress administration of N-nitrosodiethylamine. The mice were sacrificed after 12 weeks of treatment, and the status of major enzymatic and non-enzymatic antioxidants, liver function markers, lipid peroxidation and the extent of DNA damage were determined in circulation and liver tissues of all the groups. The N-nitrosodiethylamine treated group showed significantly compromised levels of the antioxidant enzymes, lipid peroxidation, and the liver function markers with enhanced DNA damage as compared to chronic unpredictable stress or control groups. A similar but less typical pattern observed in the chronic unpredictable stress treated mice. All the measured biochemical parameters were significantly altered in the group treated with the combination of chronic unpredictable stress and N-nitrosodiethylamine when compared to controls, or chronic unpredictable stress alone and/or N-nitrosodiethylamine alone treated groups. Thus, exposure to continuous, unpredictable stress conditions even in general life may significantly enhance the hepatotoxic potential of N-nitrosodiethylamine through an increase in the oxidative stress and DNA damage.

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“…Protection of cells from the lethal effects of toxic compounds was observed due to the presence of abundant amounts of glutathione which is an important determinant of cellular sensitivity to various drugs and other toxic compounds [7,8]. Depletion of GSH levels in the cells could promote tumor development in different animal species [9].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

2016

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Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn’t change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared to control group. In addition, treatment of mice with CP was found to induce the protein expression of CYP 3A4, 2B1/2, 2C6, 2C23. Moreover, the present study showed that essential oils reduced the expression of CYPs 2E1, 3A4 but could not restore the expression of CYP 2C6 and 2C23 compared to CP-treated mice. Interestingly, pretreatment of mice with essential oil of clove was found to restore activities of DMN-dI, AHH, and ECOD which were induced by CP to their normal control levels. It is concluded that EOs showed a marked hepatoprotective effect against hepatotoxicity induced by CP. In addition, co-administration of CP with any of these oils might be used as a new strategy for cancer treatment to alleviate the hepatotoxicity induced by CP.

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Liver cancer is induced by a subnecrogenic dose of DENA when associated with fasting/refeeding: role of glutathione-transferase and lipid peroxidation

Cited by 21 publications

References 38 publications

24-Hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or α-ketoglutarate

24-Hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or α-ketoglutarate

Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress

Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

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