Protective effect of treatment with thiamine or benfotiamine on liver oxidative damage in rat model of acute ethanol intoxication
Graphical abstract
Introduction
Ethanol metabolism produces free radicals and reactive oxygen species with consequent consumption of antioxidants leading to an imbalance between oxidants/antioxidants, known as oxidative stress. Several research groups have focused on the study of liver diseases caused by alcohol, since this is the organ responsible for about 95% of its catabolism [1]. The hepatic metabolism of ethanol is carried via three enzymatic pathways: pathway of alcohol dehydrogenase, the microsomal ethanol oxidation system (CYP2E1), and catalase [2], [3]. While these metabolic pathways are well elucidated in the literature, little attention is given to the quantification of ethanol in liver although this can be an important finding to know the metabolizing status of alcohol in this organ.
During the transformation of ethanol to acetaldehyde via CYP2E1 there is an overproduction of free radicals and reactive oxygen species, mainly in the forms of superoxide anion (O2‐), hydrogen peroxide (H2O2) and hydroxyethyl radical (CH3CH(•)OH) [4], [5], [6]. These molecules are highly reactive and, as acetaldehyde, attack macromolecules, causing impairment or loss of function and, ultimately, cell death [7].
The use of antioxidants may help balance the hepatic antioxidant system reducing the deleterious effects caused by oxidative stress [8].
Thiamine, the vitamin B1, is a water soluble vitamin that plays essential role on energetic metabolism from carbohydrates. Benfotiamine is a weak soluble in water pro-vitamin B1 substance that displays better absorption and bioavailability compared with common pharmaceutical form available, thiamine hydrochloride, when administered orally, even after massive ethanol administration [12]. Thiamine therapeutic replacement is postulated in patients with Wernicke encephalopathy, especially alcoholics, due to deficiency of this vitamin in this particular group, because of poor dietary habits and a reduced absorption due to changes in the gastrointestinal system [9], [10]. Hypothetically, thiamine supply could increase the metabolism of ethanol by restoring the microsomal ethanol oxidizing system (MEOS).
Studies from our group have previously demonstrated some beneficial effects on intravenous administration of thiamine in an animal model of acute ethanol intoxication and more recently the high bioavailability of benfotiamine in rats acutely alcoholized [11], [12]. In humans, benfotiamine has been tested as oral treatment of alcoholic polyneuropathy with great improvement of the symptoms [13].
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) defines binge drinking as a pattern of drinking that brings blood alcohol concentration (BAC) levels to 0.8 g/L, typically occurring after 4 drinks for women and 5 drinks for men in about 2 h [14], [15]. In experimental models this can be achieved by forced administration of a massive dose of ethanol by gavage since animals do not voluntarily consume alcohol at concentrations that produce intoxication [15]. It has been showed that, as the chronic models, the acute ethanol intoxication produces an increase in hepatic oxidative stress.
In the present study we evaluate the effects of the administration of benfotiamine or thiamine on the improvement of hepatic oxidative damage and ethanol influx in a model of acute ethanol intoxication
Section snippets
Animals and experimental protocol
Thirty male Wistar rats, weighing 270–333 g, were obtained from the Central Animal Facilities of the Ribeirão Preto Campus, University of São Paulo, and allowed to acclimate for 1 week in the animal facilities of the Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, under controlled conditions of a 12-h light: dark cycle and temperature of 24 ± 2 °C in individual cages with free access to food and water. The experimental protocol was approved by the
Results
In Table 1 we note that the groups receiving treatment with thiamine and benfotiamine had higher serum ethanol (P < 0.05) than group E + S. The same behavior was observed for liver ethanol concentrations, but with E + BE group reaching values significantly higher (P < 0.05) than the E + T group. When we analyze the percentage of hepatic ethanol relative to the initial dose, a significant difference (P < 0.05) among the three groups that received ethanol was found, with values of 1.3 ± 1.3%, 2.5 ± 0.9% and 3.6 ±
Discussion
This study aimed to evaluate the benefits of treatment with thiamine or benfotiamine against damage caused by acute ethanol administration in rats, an experimental model that produces effects similar to those caused by the massive intake (“binge drinking”) of ethanol in humans.
Although there are no reports in the literature, liver ethanol values can be auxiliary in the elucidation of the deleterious effects of hepatic metabolism of the substance. Thus, treatment with thiamine and benfotiamine
Conclusion
The treatment with thiamine or benfotiamine even 30 min after the massive dose of ethanol has proven to be beneficial against liver damage. Better results were obtained with benfotiamine related to oxidative damage from aqueous compartments.
References (29)
- et al.
Oxidative stress and antioxidant status in patients with alcoholic liver disease
Clin. Chim. Acta
(2005) Metabolism of alcohol
Clin Liver Dis
(2005)- et al.
Liver, plasma and erythrocyte levels of thiamine and its phosphate esters in rats with acute ethanol intoxication: a comparison of thiamine and benfotiamine administration
Eur. J. Pharm. Sci.
(2013) - et al.
Microsomal lipid peroxidation
Methods Enzymol.
(1978) - et al.
Free and total malondialdehyde assessment in biological matrices by gas chromatography–mass spectrometry: what is needed for an accurate detection
Anal. Biochem.
(1999) - et al.
Re-evaluation of the ferrous oxidation in xylenol orange assay for the measurement of plasma lipid hydroperoxides
J. Biochem. Biophys. Methods
(1998) - et al.
Protein oxidation in hemodialysis and kidney transplantation
Metabolism
(1996) - et al.
Advanced oxidation protein products as a novel marker of oxidative stress in uremia
Kidney Int.
(1996) - et al.
Simultaneous determination of retinol, alpha-tocopherol and beta-carotene in serum by isocratic high-performance liquid chromatography
J. Chromatogr.
(1991) - et al.
Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent
Anal. Biochem.
(1968)
Effect of an acute dose of ethanol on lipid peroxidation in rats: action of vitamin E
Food Chem. Toxicol.
The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role
Drug Metab. Rev.
Oxidative stress and alcoholic liver disease
Alcohol Health Res World
Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure
Carcinogenesis
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