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-adenosyl-L-methionine (SAM). We have investigated the possible involvement of glutathione in the protective mechanism of SAM. Firstly, we found that TAM treatment in the rat induced changes in liver glutathione disulfide (GSSG) levels, with a concomitant increase in the glutathione reductase 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 liver gene expression was completely abolished. These results were confirmed by assaying the alanine transaminase serum activity, a parameter of liver injury. TAM-treated animals had increases in this serum enzyme, this effect being partially blocked by SAM. However, in BSO-pretreated rats, the protective effect of SAM was impaired. Taking together all these results, we propose a glutathione-dependent mechanism in the SAM protection against TAM hepatotoxicity in the rat.
Mesa
M L
ML
Departamento de Bioquímica y Biología Molecular, Instituto de Bioquímica, Madrid, Spain.
Carrizosa
R
R
Martínez-Honduvilla
C
C
Benito
M
M
Fabregat
I
I
D000199:Actins / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000418:Albumins / Q000235:genetics; D000818:Animals; D019328:Buthionine Sulfoximine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism / Q000502:physiology*; D019803:Glutathione Disulfide; D005980:Glutathione Reductase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012436:S-Adenosylmethionine / Q000494:pharmacology / Q000502:physiology*; D013853:Thioacetamide / Q000633:toxicity*
D000199:Actins; D000418:Albumins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013853:Thioacetamide; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D012436:S-Adenosylmethionine; D005980:Glutathione Reductase; D000410:Alanine Transaminase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide