Changes in rat liver gene expression induced by thioacetamide: Protective role of S-adenosyl-L-methionine by a glutathione-dependent mechanism
✍ Scribed by M L Mesa; R Carrizosa; C Martinez-Honduvilla; M Benito; I Fabregat
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 453 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Chronic liver damage induced by thioacetamide
Chronic liver dysfunction caused by cirrhosis is a (TAM) was accompanied by changes in the expression relatively common disease and is accompanied by alterof genes related to growth (b-actin) and function (albuations that affect the normal function of the liver. 1 Numin and haptoglobin) of the liver. Their messenger RNA merous animal models of cirrhosis have been developed (mRNA) levels increased during the first days after TAM that more or less resemble the human disease. The administration, but 4 to 7 days after prolonged treatslowly developing thioacetamide (TAM)-induced rat ment with this drug, liver gene expression was considercirrhosis has proven to be morphologically well defined able decreased. TAM-induced changes in albumin and and uniform 2 and seems to resemble major features of b-actin mRNA levels were prevented by cotreatment the human disease. 3 S-adenosyl-L-methionine (SAM),
with S-adenosyl-L-methionine (SAM). We have investi-
the principal methyl-group donor and metabolite of megated the possible involvement of glutathione in the protective mechanism of SAM. Firstly, we found that TAM thionine, has increasingly been used in the therapy of treatment in the rat induced changes in liver glutathichronic liver disease. 4,5 SAM treatment prevents carone disulfide (GSSG) levels, with a concomitant increase bon tetrachloride 6 and acetaminophen 7 hepatotoxicity in the glutathione reductase enzymatic activity, these and produces significant reduction of hepatic necrosis changes being abolished when animals were cotreated induced by TAM. 8 The mechanism by which SAM inwith TAM and SAM. Secondly, when rats were prehibits liver disorders is poorly understood. It could be treated with buthionine sulfoximine (BSO), a glutathirelated to an increase in glutathione level induced by one synthesis inhibitor, before thioacetamide adminis-SAM in chronic liver disease 9 or to its ability to induce tration, the beneficial effect of SAM on liver gene protein methylation. 10 expression was completely abolished. These results were
The objective of our investigation has been to study confirmed by assaying the alanine transaminase serum activity, a parameter of liver injury. TAM-treated ani-the changes in liver gene expression after short-term mals had increases in this serum enzyme, this effect be-TAM administration in the rat, and the possible protecing partially blocked by SAM. However, in BSO-pretive effect of SAM on these alterations. We have setreated rats, the protective effect of SAM was impaired. lected two genes, albumin and b-actin, as markers of Taking together all these results, we propose a glutathiliver function and growth, respectively. Production of one-dependent mechanism in the SAM protection plasma proteins is one of the main liver functions. Seagainst TAM hepatotoxicity in the rat. (HEPATOLOGY rum albumin is the most abundant protein synthesized 1996;23:600-606.) by liver cells, and its concentration increases from low levels early in fetal development to a high plateau in adulthood. During liver regeneration after partial hep-Abbreviations: TAM, thioacetamide; SAM, S-adenosyl-L-methionine; mRNA, messenger RNA; [a-32 P]dCTP, [a-32 P]deoxy-cytidine triphosphate; atectomy, albumin messenger RNA (mRNA) level re-BSO, buthionine sulfoximine; NADPH, reduced form of nicotinamide-adenine mains essentially constant, or even increases, during dinucleotide phosphate; GSSG, gluthathione disulfide; GSH, glutathione; gthe first 24 hours. 11 According to these results, we have GCS, g-glutamylcysteine synthetase.
recently shown that under proliferative conditions (i.e., From the Departamento de Bioquı ´mica y Biologı ´a Molecular, Instituto de in the presence of epidermal growth factor, fetal