S-Adenosylmethionine (SAMe) attenuates acetaminophen hepatotoxicity in C57BL/6 mice

Valentovic, Monica; Terneus, Marcus; Harmon, R. Christopher; Carpenter, A. Betts

doi:10.1016/j.toxlet.2004.07.010

Cited by 26 publications

(33 citation statements)

References 24 publications

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“…S-Adenosyl-L-methionine (SAMe) has been shown to reduce APAP hepatotoxicity by our laboratory (Valentovic et al, 2004) as well as others (Stramentinoli et al, 1979;Bray et al, 1992;Carrasco et al, 2000;Song et al, 2003). SAMe administration just before APAP treatment greatly diminished the extent of centrilobular necrosis in C57BL/6 male mice compared with animals given APAP (Valentovic et al, 2004).…”

Section: Acetaminophen (Apap) or N-(4-hydroxyphenyl Acetamide)mentioning

confidence: 85%

Comparison of S-Adenosyl-l-methionine and N-Acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity

Terneus

Kiningham²,

Carpenter³

et al. 2006

J Pharmacol Exp Ther

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Nutraceuticals are widely used by the general public, but very little information is available regarding the effects of nutritional agents on drug toxicity. Excessive doses of acetaminophen (APAP, 4-hydroxyacetanilide) induce hepatic centrilobular necrosis. The naturally occurring substance S-adenosyl-L-methionine (SAMe) has been reported to reduce the hepatic toxicity of APAP. The present study was designed to investigate the hepatoprotective effects of SAMe in comparison to the clinically used antidote N-acetylcysteine (NAC). Male C57BL/6 mice were injected intraperitoneally (i.p.) with an equimolar dose (1.25 mmol/kg) of either SAMe or NAC just before APAP, and the groups were denoted SAMeϩAPAP and NACϩAPAP, respectively. Mice were immediately injected i.p. with 300 mg/kg APAP, and hepatotoxicity was evaluated after 4 h. SAMe was more hepatoprotective than NAC at a dose of 1.25 mmol/kg as liver weight was unchanged by APAP injection in the SAMeϩAPAP group, whereas liver weight was increased in the NACϩAPAP group. SAMe was more hepatoprotective for APAP toxicity than NAC, because alanine aminotransferase levels were lower in the SAMeϩAPAP. Pretreatment with SAMe maintained total hepatic glutathione (GSH) levels higher than NAC pretreatment before APAP, although total hepatic GSH levels were lower in the SAMeϩAPAP and NACϩAPAP groups than the vehicle control values. Oxidative stress was less extensive in the SAMeϩAPAP group compared with the APAPtreated mice as indicated by Western blots for protein carbonyls and 4-hydroxynonenal-adducted proteins. In summary, SAMe reduced APAP toxicity and was more potent than NAC in reducing APAP hepatotoxicity.

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Section: Acetaminophen (Apap) or N-(4-hydroxyphenyl Acetamide)mentioning

confidence: 85%

Comparison of S-Adenosyl-l-methionine and N-Acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity

Terneus

Kiningham²,

Carpenter³

et al. 2006

J Pharmacol Exp Ther

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“…Oxidized-LDL bound to HNE-adducted apoB has a lower affinity for the apoB/E receptors that are expressed in most cell lines, except macrophages. Such modified LDLs are then reoriented toward scavenger receptors, expressed at the surface of macrophages and smooth muscle cells, leading to the Low levels of HNE in tumor tissues compared with healthy tissues, rTGFb1 [46][47][48]49 High levels of HNE in cancer tissues [50][51][52][53][54][55] Luminal HNE triggers the positive selection of preneoplastic cells in colorectal cancer 14,59 Atherosclerosis 37 The subsequent atheromatous plaque formation involves macrophage infiltration and activation of smooth muscle cells leading to fibrogenesis. HNE can particularly form adducts with PDGFR (platelet-derived growth factor receptor) in atherosclerotic aortas and the use of the antioxidant hydralazine prevents HNE-related adduction and slows the progression of the disease.…”

Section: Hne and Diseases Associated With Oxidative Damage: Links To mentioning

confidence: 99%

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

et al. 2013

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During the last three decades, 4-hydroxy-2-nonenal (HNE), a major a,b-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.

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“…The depletion of liver GSH itself can lead to inactivation of MAT, the key enzyme in SAMe synthesis. Moreover, the decrease of GSH alleviated by SAMe was accompanied by attenuation of lipid peroxidation (Valentovic et al 2004).…”

mentioning

confidence: 91%

“…It was clearly documented that liver necrosis induced by AAP in the mouse was improved by SAMe (Bray et al 1992;Valentovic et al 2004) as evidenced by a reduction of AAPelevated activity of serum ALT and AST and from histological analysis. Nevertheless, there is a lack of data concerning the protective effect of SAMe against AAP hepatotoxicity in cell culture.…”

mentioning

confidence: 97%

Effect of S-adenosylmethionine on Acetaminophen-induced Toxic Injury of Rat Hepatocytes in vitro

et al. 2009

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Acetaminophen (AAP) overdose causes severe liver injury and is the leading cause of acute liver injury in humans. The mechanisms participating in its toxic effect are glutathione depletion, oxidative stress and mitochondrial dysfunction. S-adenosylmethionine (SAMe) is the principal biological methyl donor and is also a precursor of glutathione. In our previous studies we have documented a protective action of SAMe against various toxic injuries of rat hepatocytes in primary cultures. The aim of this study was to evaluate a possible protective effect of SAMe against AAP-induced toxic injury of primary rat hepatocytes. Hepatocytes were exposed to AAP (2.5 mM) or AAP together with SAMe at the final concentrations of 5, 25 or 50 mg/l for 24 h. Incubation of hepatocytes with AAP caused a significant increase of the leakage of lactate dehydrogenase (LDH) (p < 0.001) and decline of the activity of cellular dehydrogenases (WST-1) (p < 0.001). Co-incubation of hepatocytes with SAMe at any dose did not improve these markers of cellular integrity. The functional indicators improved in hepatocytes co-cultured with SAMe -urea production was significantly increased when using the highest dose of SAMe (p < 0.05); albumin synthesis was higher in all cultured hepatocytes exposed to SAMe (p < 0.05). SAMe did not influence AAP-induced decrease of cellular content of glutathione. Mitochondrial respiration of harvested digitonin-permeabilized hepatocytes was measured; Complex II was more sensitive to toxic action of AAP, respiration was decreased by 20%. This decrease was completely abolished by SAMe. Hepatotoxicity, hepatoprotective effect, mitochondrial membrane potential, urea, albumin, glutathione, LDHAcetaminophen (AAP) is a widely used, relatively safe analgesic/antipyretic drug. Nevertheless, AAP overdose causes centrilobular necrosis of the liver and is the leading cause of acute liver injury in humans in the United States and most of Europe (Lee 2007). The primary metabolic pathway for AAP is glucuronidation and sulphation in the liver; this yields relative non-toxic metabolites, which are excreted into bile (Mitchell et al. 1973). AAP hepatotoxicity is dependent on another metabolic pathway. The remaining part of AAP dose, which is not directly conjugated with the hydrophylic group, is biotransformed by the cytochrome P450 family to an electrophilic, highly reactive metabolite N-acetylp-benzoquinone imine (NAPQI), which is detoxified by glutathione (Jaeschke and Bajt 2006). However, if the formation of NAPQI exceeds the capacity of liver glutathione (GSH), this reactive metabolite forms covalent adducts primarily with cysteine residues on various cellular proteins (Nelson and Bruschi 2003; Allameh and Alikhani 2006). The most important mechanism of AAP-induced cell death seems to be a change in the function of critical cellular proteins due to covalent bindings. Numerous cytosolic, mitochondrial, ribosomal, microsomal, and nuclear proteins bound to AAP have been identified. Nevertheless, the primary cellular targe...

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S-Adenosylmethionine (SAMe) attenuates acetaminophen hepatotoxicity in C57BL/6 mice

Cited by 26 publications

References 24 publications

Comparison of S-Adenosyl-l-methionine and N-Acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity

Comparison of S-Adenosyl-l-methionine and N-Acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

Effect of S-adenosylmethionine on Acetaminophen-induced Toxic Injury of Rat Hepatocytes in vitro

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