Carbon tetrachloride–induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: Effect ofS-adenosylmethionine treatment

Abstract

Carbon tetrachloride (CCl,) administration to rats produces hepatic cirrhosis and supplementation with Sadenosylmethionine (SAM) can partially prevent CCLinduced liver injury. These effects are thought to be caused by oxidative stress and the subsequent formation of free radicals, but the mechanism whereby this occurs and the accurate nature of the mechanisms by which SAM exerts its protective action are not well understood.The effect of short-term administration of CCl, on hepatic DNA methylation and on S A M and S-adenosylhomocysteine (SAH) were assessed. CCl, administration to rats for 3 weeks resulted in hypomethylation of liver DNA, determined by comparing the extent to which DNA from livers of control or treated animals could be methylated in uitro using [3H-methyl] Carbon tetrachloride (Cch), a toxic agent commonly used for the study of liver diseases in different experimental animal models, is a substrate for P-450 where it is converted to CC1, radicals, which generate CC1300 radicals by reacting with molecular oxygen. Because CC1, radicals react with membranes and induce lipid peroxidation, membrane damage by free radical chain reaction has been proposed as the major cause of hepatocellular injury by CC14, the probable initial event being mitochondria1 membrane injury. ' We have previously shown that administration of CCl, to rats for 3 weeks produces liver steatosis.' When CC14 administration was maintained for 6 additional weeks, the majority of the animals had developed cirrhosis. The later histological alterations were accompanied by a decrease of hepatic S-adenosylmethionine (SAM) synthetase activity and glutathione (GSH) depletion. ' The above results were partially corrected by the administration of exogenous SAM, but the mechanism whereby this occurs and the accurate nature of the mechanisms by which SAM exerts its protective action are not well understood. SAM serves as the donor of methyl groups in many transmethylation reactions (e.g., DNA-, phospholipid-, and protein-methylation).In donating its methyl group, SAM is converted to Sadenosylhomocysteine (SAH), which in turn is hydrolyzed to homocysteine and adenosine. Homocysteine can then be remethylated to methionine (via Blz-dependent methionine synthase or additionally in liver by betaine homocysteine methyltransferase) or degraded via the transsulphuration pathway. The transsulphuration pathway is the principal mechanism by 1310

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

“…As shown in Fig. 5, and in agreement with previous reports [13], we observe a statistically significant reduction in the level of overall DNA methylation in the cirrhotic livers. Interestingly, DNA methylation levels were recovered in the IGF-I-treated rats (Fig.…”

“…Asterisk (*) indicates P < 0.05 with respect to CO values. els of CCl 4 -induced cirrhosis in rats [13]. Changes in this covalent modification of DNA can participate in the alterations in gene expression observed in chronic liver damage.…”

“…IGF-I treatment partially normalized the expression of eight of these genes. In addition, this growth factor was capable of restoring global DNA methylation at CpG sites, that is reduced in the cirrhotic liver [13]. This latter effect of IGF-I, together with the nature of some of the identified genes, suggest that the hepatoprotective action of this growth factor is mediated in part at the level of gene expression.…”

Cirrose experimental induzida pela inalação de tetracloreto de carbono: adaptação da técnica e avaliação da peroxidação lipídica

“…A colchicina, por exemplo, foi capaz de reduzir significativamente a peroxidação lipídica em ratos cirróticos por CCl 4 intraperitonial, porém sem produzir efetiva proteção contra a fibrogênese (16,23) . A avaliação das enzimas catalase, superóxido dismutase e glutationa poderiam ser de grande utilidade para a avaliação do comportamento das defesas antioxidantes do organismo, diante de situação capaz de provocar cirrose hepática (17,32) . Estudos recentes têm demonstrado que o uso de flavonóides, tipo rutina e quercitina, na cirrose biliar secundária por ligadura do ducto biliar em ratos, reduz marcadamente a lesão hepática, melhorando as provas de função hepática (AST, ALT e fosfatase alcalina) e diminuindo a lipoperoxidação, inibindo a proliferação de ducto biliar e atenuando a fibrose hepática (25) .…”

S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signalingin vitro

“…AdoMet depletion has been observed in a number of experimental models of liver diseases associated with increased oxidative stress and a depletion of reduced glutathione (GSH). [21][22][23][24] Oral AdoMet treatment has therefore been used in animal models and in patients to restore GSH content in the liver with the aim to treat liver diseases. [25][26][27] We were interested in AdoMet not because of its role in GSH biosynthesis, 28,29 but because PRMT1 uses AdoMet as the methyl group donor for STAT1 methylation (Fig.…”