Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat

Vendemiale, Gianluigi; Grattagliano, Ignazio; Altomare, Emanuele; Turturro, Nicola; Guerrieri, Ferruccio

doi:10.1016/0006-2952(96)00414-5

Cited by 83 publications

(48 citation statements)

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“…Changes in cell energy metabolism and mitochondrial dysfunction have been observed after acetaminophen administration. The influence of AAP on respiration probably depends on AAP concentration and on the time of exposure (Vendemiale et al 1996). Our results suggest that AAP inhibits mitochondrial respiration by site-specific manner.…”

Section: Discussionmentioning

confidence: 65%

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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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Section: Discussionmentioning

confidence: 65%

“…Mitochondria have been documented to play an important role in the AAP-induced liver injury (Vendemiale et al 1996;Burcham and Harman 1991;Masubuchi et al 2005). Oxidative stress promotes MPT (Reid et al 2005) characterised by a decrease of mitochondrial membrane potential (MMP).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…18 Cellular oxidative stress has been often associated with impairment of mitochondrial respiration and energy production in histologically normal liver. 11,29,34,35 We have recently shown that the decrease of mitochondrial GSH, which occurs during aging, 36,37 in the early phase of liver regeneration after partial hepatectomy, 29,34,37 or following acetaminophen administration, 35 impairs several mitochondrial functions, such as oxidative phosphorylation 29 and amino acid decarboxylation, 38 and leads to oxidative damage of the F 0 F 1 -ATP synthase complex. 29,34 In the case of fatty liver, these aspects deserve even more careful considerations because the reduced tolerance of steatotic livers to the injury associated with important surgical procedure, such as liver transplantation 1 or partial hepatectomy, 39 and clinical conditions, such as drug administration and aging, would suggest a reduced efficiency of the energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status

et al. 2001

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Hepatic steatosis is associated with mitochondrial oxidative alterations. This study aimed to characterize in a choline-deficient model of rat fatty liver whether this oxidative imbalance is related to an impairment of the capacity of ATP synthesis both under fed conditions and after starvation, which may sensitize mitochondria to oxidative injury. Mitochondria were isolated from normal and fatty livers of fed or 18-hour fasted rats. Oxidative injury was evaluated by measuring the mitochondrial content of thiobarbituric reactive substances, protein carbonyls, glutathione, and protein sulfhydryls. The mitochondrial F 0 F 1 -ATP synthase content, tissue ATP concentration, and liver histology were also determined. Compared with normal liver, under fed conditions, fatty livers showed a greater mitochondrial content of oxidized lipids and proteins together with a low concentration of sulfhydryls and glutathione. The mitochondrial catalytic ␤-F 1 subunit of the F 0 F 1 -ATP synthase was about 35% lower in fatty livers. Hepatic ATP was also significantly reduced in fatty liver. Starvation exacerbated mitochondrial oxidative injury in both groups but to a greater extent in fatty livers. In the steatotic group, fasting induced a significant decrease of the ATP levels, which was accompanied by a 70% fall of the catalytic ␤-F 1 subunit. These data indicate that the mitochondrial oxidative alterations in fatty livers are associated with an important reduction of the F 0 F 1 -ATP synthase. These changes, which are greatly exacerbated after starvation, may account for the reduced synthesis of the hepatic ATP observed in the presence of fatty infiltration. (HEPATOLOGY 2001;33:808-815.)Hepatic steatosis without concomitant inflammation or fibrosis, is usually considered a benign condition. However, fatty degeneration increases the sensitivity of the liver to several types of injury, such as those due to ischemia-reperfusion 1 or drug toxicity. 2 Fatty infiltration is associated with a number of intracellular disorders, which can be either a cause or a consequence of lipid accumulation. 3 Among them, mitochondrial abnormalities related to an increased generation of reactive oxygen species have been described in human steatosis of various etiology (alcoholic 4 and nonalcoholic steatohepatitis, 5 iron, 6 or copper 7 overload) and in several experimental models of fatty liver, including alcohol administration 8 and drug toxicity. 2,9 Mitochondrial oxidative injury has been also described in conditions of chronic administration of commonly used drugs, such as valproate 10 or amiodarone, 11 the hepatic metabolites of which are known to interfere with mitochondrial respiration and fatty acid metabolism, thus producing fatty degeneration.Oxidative metabolism in mitochondria represent the main source of energy for the cells. Alterations of specific mitochondrial functions may, therefore, lead to an impaired production of ATP and a reduced uptake of substrates for mitochondrial metabolism 12 and eventually limit resistance and survival o...

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“…6, A and B). Because mitochondrial GSH levels have been reported to decrease early after APAP administration in rats (Vendemiale et al, 1996), we investigated the effect of a 1-h exposure to APAP, in vivo, on mitochondrial and cytosolic levels of GSH in both wild-type and Cyp2e1(Ϫ/Ϫ) mice. In these experiments, APAP was administered at doses at which EIP pretreatment increased APAP hepatotoxicity (300 mg/kg in wildtype mice and 600 mg/kg in Cyp2e1(Ϫ/Ϫ) mice) (Fig.…”

Section: Downloaded Frommentioning

confidence: 99%

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Wolf¹,

Wood²,

Allard³

et al. 2007

Drug Metab Dispos

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ABSTRACT:CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(؊/؊) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(؊/؊) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(؊/؊) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(؊/؊) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(؊/؊) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.Acetaminophen (APAP) is considered to be a relatively safe drug and is widely prescribed and used for its analgesic and antipyretic properties. The first reports of hepatotoxicity in humans resulting from APAP overdose were in 1966 ( Thomson and Prescott, 1966). Today, APAP is a frequent cause of liver failure and the leading cause of death due to accidental and deliberate overdose (for review, see Bromer and Black, 2003). APAP is mainly glucuronidated and sulfated in the liver by phase II metabolic pathways, leading to excretion of the drug. However, APAP is also metabolized by certain forms of cytochromes P450 (P450s) to N-acetyl-p-benzoquinone imine (NAPQI), a highly electrophilic metabolite that is considered to be responsible for triggering the ensuing liver damage. CYP1A2, CYP2E1, and CYP3A are three forms of rat and human P450s active in the conversion of APAP to NAPQI, with CYP2E1 and CYP3A having greater intrinsic activity than CYP1A2 (Patten et al., 1993;Thummel et al., 1993). Reduced glutathione (GSH) reacts with NAPQI, resulting in the inactivation of this reactive metabolite. When GSH levels become depleted, liver damage can occur as a result of the

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Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat

Cited by 83 publications

References 32 publications

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

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

Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

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