The effectiveness of N-acetylcysteine in isolated hepatocytes, against the toxicity of paracetamol, acrolein, and paraquat

Dawson, Janet R.; Norbeck, Kajsa; Anundi, Iréne; Moldéus, Peter

doi:10.1007/bf00316579

Cited by 78 publications

(31 citation statements)

References 22 publications

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“…The mechanism of protection could be stimulation of glutathione synthesis or substitution of glutathione in oxidative or covalent binding reactions as previously reported by Dawson et al (1984). Thus, the effects of N-acetylcysteine support the hypothesis that intracellular glutathione homeostasis was affected by valproic acid.…”

Section: Discussionsupporting

confidence: 83%

Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

Klee¹,

Johanssen

Ungemach

2000

Pharmacology & Toxicology

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The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.

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Section: Discussionsupporting

confidence: 83%

Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

Klee¹,

Johanssen

Ungemach

2000

Pharmacology & Toxicology

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“…These results suggest that GSH played a key role in the activation of chromium(VI) to species capable of causing DNA strand breaks. Although GSH is usually thought to protect cells from the toxic effects of agents such as acetaminophen (25), benzo[a]pyrene (26), and radiation (27), it is also known to activate mutagens such as N-hydroxy-3-amino-1-methyl-5H-pyrido [4,3-b]indole (28), 1,2-dibromoethane (29,30), 1,2-dichloroethane (31), N-methyl-and N-ethyl-N'-nitro-N-nitrosoguanidine (29). GSH has been shown to be important for reduction of chromium(VI) in rat liver in vivo (14).…”

Section: Discussionmentioning

confidence: 99%

Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes.

Cupo¹,

Wetterhahn²

1985

Proc. Natl. Acad. Sci. U.S.A.

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The role ofglutathione and cytochrome P-450 in the production of DNA damage by chromium(VI) was examined In chicken embryo hepatocytes by the alkaline elution technique. Cellular levels of glutathione and cytochrome P-450 were altered by treating the hepatocytes with N-acetyl-Lcysteine, buthionine sulfoximine, isopentanol, or 8-naphthoflavone. A dramatic increase in chromium(VI)-induced DNA strand breaks was observed after increasing glutathione levels in the cells. Chromium(VI)-induced DNA strand breaks were even more numerous when the level of cytochrome P-450 was also increased. Upon depletion of glutathione levels and induction ofcytochrome P-450 or cytochrome P 448, little or no DNA strand breaks or DNA interstrand cross-links were observed after chromium(VI) treatment. Chromium(VI)-induced DNA-protein cross-links generally decreased after either increases or decreases in cellular levels of glutathione or cytochrome P-450 or P-448. These results suggest that glutathione enhances chromium(VI)-induced DNA damage through metabolic activation of chromium(VI). The possible production of reactive chromium species upon metabolism by glutathione and cytochrome P-450 or P448 and their involvement in DNA damage is discussed.Chromium(VI) compounds are recognized as carcinogens in humans and animals (1) and as mutagens in bacterial and mammalian cell systems (2). Chromium(VI) causes DNA strand breaks and cross-links in vivo and in cultured cells (3)(4)(5)(6). It has been proposed that cellular metabolism of chromium(VI) compounds is necessary for DNA damage, since chromium(VI) does not react with isolated DNA under physiological conditions (7). The DNA-damaging ability of other carcinogenic agents has been shown to be modulated by metabolic pathways such as the cytochrome P450 system, sulfotransferases, and glutathione (GSH) (8). Changes in cellular levels of cytochromes P-450 alter the levels of DNA damage produced by carbon tetrachloride (9), benzo-[a]pyrene (10), and dimethylnitrosamine (11) in rodents.In vitro studies have identified several cellular components that are capable of metabolizing chromium(VI) (12-14). Rat liver microsomes contain a NADPH-dependent chromium(VI) reductase activity (15). Induction of cytochrome(s) P-450 by phenobarbital enhances the chromium(VI) reductase activity ofliver microsomes; however, induction of cytochrome(s) P-448 by 3-methylcholanthrene has no effect (13). GSH also reduced chromium(VI) in vitro under physiological conditions (12,14). The reaction of GSH with chromium(VI) has been proposed to occur by a two-step mechanism that involves the rapid formation of a chromium(VI) thioester followed by the reduction of the chromium(VI) thioester to chromium(III) (12).The present report describes the effect of altering the intracellular concentrations of cytochrome P450 and P-448 and GSH on chromium(VI)-induced DNA damage in primary cultured chicken embryo hepatocytes. Chromium(VI) treatment is known to produce DNA damage in chicken embryo hepatocytes (5, 6). The hepatocytes ar...

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“…Acetylcysteine: pharmacodynamic properties Acetylcysteine prevents GSH depletion and minimizes hepatocyte injury caused by a number of different toxins [Dawson et al 1984]. Animal studies of paracetamol-induced liver injury suggest that a primary mechanism of acetylcysteine is the provision of cysteine to stimulate replenishment of GSH to allow detoxification of NAPQI [Viña et al 1980;Lin and Levy, 1981;Massey and Racz, 1981].…”

Section: Glutathione Donorsmentioning

confidence: 99%

Novel acetylcysteine regimens for treatment of paracetamol overdose

Waring

2012

Therapeutic Advances in Drug Safety

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Pathophysiology of paracetamol-induced liver injuryAcute paracetamol administration is associated with significant depletion of glutathione (GSH), attributed to covalent binding of an intermediate paracetamol metabolite, N-acetyl-p-benzoquinone imine (NAPQI) to critical proteins and enzymes within hepatocytes. Restoration of intrahepatic glutathione concentrations in animals minimized the extent of NAPQI covalent binding to Novel acetylcysteine regimens for treatment of paracetamol overdose W. Stephen Waring Abstract: Paracetamol (acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose. Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment. The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations. This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury. Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.

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The effectiveness of N-acetylcysteine in isolated hepatocytes, against the toxicity of paracetamol, acrolein, and paraquat

Cited by 78 publications

References 22 publications

Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity

Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes.

Novel acetylcysteine regimens for treatment of paracetamol overdose

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