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

Mar 15, 2008Redox report : communications in free radical research

Daily patterns of oxidative stress during liver cancer development in rats and the effects of melatonin or alpha-ketoglutarate

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Abstract

N-nitrosodiethylamine (NDEA) treatment increased liver enzyme activity and lipid peroxidation while decreasing antioxidant levels in rats.

NDEA administration enhanced the 24-hour rhythmic patterns of liver enzymes, specifically aspartate transaminase (AST) and alanine transaminase (ALT).
Plasma levels of alpha-fetoprotein (alpha-FP) increased following NDEA exposure.
NDEA treatment resulted in elevated levels of lipid peroxidation markers (TBARS) and reduced levels of the antioxidant reduced glutathione (GSH).
Activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST), were decreased by NDEA.
Co-administration of melatonin or alpha-ketoglutarate (alpha-KG) appeared to mitigate some harmful effects of NDEA on oxidative stress rhythms.
Melatonin specifically reduced plasma TBARS levels and increased SOD activity.

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

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