Abstract
Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.
Highlights
The increased use of drugs in medical care has become the prominent cause of liver injury [1, 2]
It is understood that depletion of intracellular antioxidant defences, especially the levels of GSH remains the critical factor implicated in the worsening of hepatic injury, in response to drug overdose
Current research indicates that exogenous administration of GSH in mice can protect against acetaminophen-induced liver injury [101]
Summary
The increased use of drugs in medical care has become the prominent cause of liver injury [1, 2]. Oxidative Medicine and Cellular Longevity supplements that may develop from asymptomatic liver test elevations to induce acute liver failure [7] The latter is by far the most common manifestation, said to be responsible for more than 90% cases of DILI [8, 9]. Because of its strong antioxidant properties and its known capacity to enhance intracellular GSH levels, N-acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against diverse diseases [16,17,18,19], besides being a drug of choice to protect against paracetamol-induced liver injury [19]. Information relevant to the therapeutic potential of NAC to modulate oxidative stress to protect against DILI, beyond paracetamol-induced liver injury, is discussed
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