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Nutrition and Supplements
The mechanism of action of N-acetylcysteine (NAC)
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<blockquote data-quote="madman" data-source="post: 208889" data-attributes="member: 13851"><p><strong>ABSTRACT</strong></p><p></p><p><em>Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is the standard of care to treat paracetamol intoxication and is included on the World Health Organization’s list of essential medicines. Additionally, NAC increasingly became the epitome of an “antioxidant”. Arguably, it is the most widely used “antioxidant” in experimental cell and animal biology, as well as clinical studies. Most investigators use and test NAC with the idea that it prevents or attenuates oxidative stress. Conventionally, it is assumed that NAC acts as (i) a reductant of disulfide bonds, (ii) a scavenger of reactive oxygen species, and/or (iii) a precursor for glutathione biosynthesis. While these mechanisms may apply under specific circumstances, they cannot be generalized to explain the effects of NAC in a majority of settings and situations<strong>.</strong> In most cases, the mechanism of action has remained unclear and untested. In this review, we discuss the validity of conventional assumptions and the scope of a newly discovered mechanism of action, namely the conversion of NAC into hydrogen sulfide and sulfane sulfur species. The antioxidative and cytoprotective activities of per- and polysulfides may explain many of the effects that have previously been ascribed to NAC or NAC-derived glutathione.</em></p><p></p><p></p><p></p><p></p><p><strong>1. Introduction: the popularity of N-acetylcysteine </strong></p><p><strong></strong></p><p><strong>2. Three classical narratives </strong></p><p><em>2.1. The disulfide reductant narrative</em></p><p><em>2.2. The oxidant scavenger narrative</em></p><p><em>2.3. The glutathione replenishment narrative </em></p><p></p><p><strong>3. Why use NAC rather than cysteine?</strong></p><p><strong></strong></p><p><strong>4. Hydrogen sulfide: the missing link in cysteine toxicity?</strong></p><p><strong></strong></p><p><strong>5. How does NAC circumvent the problem of cysteine toxicity?</strong></p><p><strong></strong></p><p><strong>6. Are the cytoprotective effects of NAC caused by low-level H2S production?</strong></p><p><strong></strong></p><p><strong>7. Are the cytoprotective effects of NAC caused by sulfane sulfur species?</strong></p><p><strong></strong></p><p><strong>8. The sulfane sulfur perspective: a new angle to look at the classical NAC narratives</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>9. Conclusion </strong></p><p></p><p><em><strong>In summary, previously favored explanations for the mechanism of action of NAC are either poorly supported (direct oxidant scavenging), restricted to very specific situations (disulfide reduction in lung mucins), or fail to explain all observations (GSH biosynthesis).<u> A new conceptual framework for NAC’s mechanism of action is emerging, namely, as a Cys pro-drug that leads to modest elevations of H2S and sulfane sulfur species inside cells</u>. <u>The slow release of Cys from NAC allows for sustained sulfane sulfur production, providing protective effects -independently of GSH replenishment (Fig. 9)</u>. The sulfane sulfur branch of NAC metabolism opens new perspectives on its therapeutic use.</strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 208889, member: 13851"] [B]ABSTRACT[/B] [I]Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is the standard of care to treat paracetamol intoxication and is included on the World Health Organization’s list of essential medicines. Additionally, NAC increasingly became the epitome of an “antioxidant”. Arguably, it is the most widely used “antioxidant” in experimental cell and animal biology, as well as clinical studies. Most investigators use and test NAC with the idea that it prevents or attenuates oxidative stress. Conventionally, it is assumed that NAC acts as (i) a reductant of disulfide bonds, (ii) a scavenger of reactive oxygen species, and/or (iii) a precursor for glutathione biosynthesis. While these mechanisms may apply under specific circumstances, they cannot be generalized to explain the effects of NAC in a majority of settings and situations[B].[/B] In most cases, the mechanism of action has remained unclear and untested. In this review, we discuss the validity of conventional assumptions and the scope of a newly discovered mechanism of action, namely the conversion of NAC into hydrogen sulfide and sulfane sulfur species. The antioxidative and cytoprotective activities of per- and polysulfides may explain many of the effects that have previously been ascribed to NAC or NAC-derived glutathione.[/I] [B]1. Introduction: the popularity of N-acetylcysteine 2. Three classical narratives [/B] [I]2.1. The disulfide reductant narrative 2.2. The oxidant scavenger narrative 2.3. The glutathione replenishment narrative [/I] [B]3. Why use NAC rather than cysteine? 4. Hydrogen sulfide: the missing link in cysteine toxicity? 5. How does NAC circumvent the problem of cysteine toxicity? 6. Are the cytoprotective effects of NAC caused by low-level H2S production? 7. Are the cytoprotective effects of NAC caused by sulfane sulfur species? 8. The sulfane sulfur perspective: a new angle to look at the classical NAC narratives 9. Conclusion [/B] [I][B]In summary, previously favored explanations for the mechanism of action of NAC are either poorly supported (direct oxidant scavenging), restricted to very specific situations (disulfide reduction in lung mucins), or fail to explain all observations (GSH biosynthesis).[U] A new conceptual framework for NAC’s mechanism of action is emerging, namely, as a Cys pro-drug that leads to modest elevations of H2S and sulfane sulfur species inside cells[/U]. [U]The slow release of Cys from NAC allows for sustained sulfane sulfur production, providing protective effects -independently of GSH replenishment (Fig. 9)[/U]. The sulfane sulfur branch of NAC metabolism opens new perspectives on its therapeutic use.[/B][/I] [/QUOTE]
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The mechanism of action of N-acetylcysteine (NAC)
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