CHANGES IN RAT-LIVER GENE-EXPRESSION INDUCED BY THIOACETAMIDE - PROTECTIVE ROLE OF S-ADENOSYL-L-METHIONINE BY A GLUTATHIONE-DEPENDENT MECHANISM

Chronic liver damage induced by thioacetamide (TAM) was accompanied by changes in the expression of genes related to growth (beta-actin) and function (albumin and haptoglobin) of the Liver. Their messenger RNA (mRNA) levels increased during the first days after TAM administration , but 4 to 7 days after prolonged treatment with this drug, Liver gene expression was considerable decreased. TAM-induced changes in albumin and beta-actin mRNA levels were prevented by cotreatment with S-adeno syl-L-methionine (SAM). We have investigated the possible involvement of glutathione in the protective mechanism of SAM. Firstly, we found t hat TAM treatment in the rat induced changes in liver glutathione disu lfide (GSSG) levels, with a concomitant increase in the glutathione re ductase enzymatic activity, these changes being abolished when animals were cotreated with TAM and SAM. Secondly, when rats were pretreated with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, before thioacetamide administration, the beneficial effect of SAM on L iver gene expression was completely abolished. These results were conf irmed by assaying the alanine transaminase serum activity, a parameter of liver injury. TAM-treated animals had increases in this serum enzy me, this effect being partially blocked by SAM. However, in BSO-pretre ated rats, the protective effect of SARI was impaired. Taking together all these results, we propose a glutathione-dependent mechanism in th e SAM protection against TAM hepatotoxicity in the rat.