Hepatotoxicity oxidative stress

Jaeschke, H. (1990). Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo-, the protective effect of allopurinol. J. Pharmacol Exp. Ther. 255, 935-941. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Analogues of paracetamol, which are unable to undergo covalent binding to protein, are still hepatotoxic and can undergo a redox reaction with GSH. However, oxidative stress has not been demonstrated in vivo, and there are differences between in vivo data and that obtained in isolated hepatocytes. 

Mehta, A., Flora, S.J.S. (2001). Possible role of metal redistribution, hepatotoxicity and oxidative stress in chelating agents induced hepatic and renal metallothionein in rats. Food. Chem. Toxicol. 39 1029-38. 

Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson JA. Mechanisms of acetaminophen-induced hepatotoxicity Role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther 2005 312 509-16. 

Ciclosporin can cause cholestasis and cellular necrosis by an inhibitory effect on hepatocyte membrane transport proteins at both sinusoidal and canalicular levels. It induces oxidative stress by accumulation of various free radicals. Ademetionine (5-adenosylmethionine) is a naturally occurring substance that is involved in liver detoxification processes. The efficacy of ademetionine in the treatment and prevention of ciclosporin-induced cholestasis has been studied in 72 men with psoriasis (89). The patients who were given ciclosporin plus ademetionine had low plasma and erythrocyte concentrations of oxidants and high concentrations of antioxidants. The authors concluded that ademetionine may protect the hver against hepatotoxic substances such as ciclosporin. 

Acetaminophen provides another example of an analogous in vitro multi-hit process. Previously, most of the acetaminophen-induced hepatotoxicity research focused on the reactive metabolite of acetaminophen, which led to covalent protein modification (reviewed in Reference 76). Recently, it was realized that mitochondrial damage and oxidative stress may be the second-hit leading to acetaminophen-induced liver injury.7778 This is substantiated by animal studies where partial knockdown of SOD2 in rats, as well as mice heterozygous to SOD2 were more susceptible to acetaminophen-induced liver injury than wild type animals.79-80... 

It therefore appears that both covalent (e.g. alkylation) and noncovalent (e.g. oxidative stress) interactions play a major role in the pathogenesis of acute lethal cell injury caused by NAPQl. At present, it is not possible to identify which of these two interactions is the critical event in initiating acetaminophen hepatotoxicity, even if some authors suggest that the characteristic features of oxidative stress are more likely the consequences of damage mediated by protein adduction. ... 

Chang, T. K., Abbott, E S. Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity. Drug Metab. Rev. 2006, 38, 627-639. 

GIBSON, F.D., PUMFORD, N.R., SAMOKYSZYN, V. M. and HINSON, J.A. (1996) Mechanism of acetaminophen-induced hepatotoxicity Covalent binding versus oxidative stress. Chem. Res. 

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