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. 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.

大约 60 年前，半胱氨酸前药 N-乙酰半胱氨酸 (NAC) 最初被用作粘液溶解剂，是治疗扑热息痛中毒的标准治疗方法，并被列入世界卫生组织的基本药物清单。此外，NAC 越来越成为“抗氧化剂”的缩影。可以说，它是实验细胞和动物生物学以及临床研究中使用最广泛的“抗氧化剂”。大多数研究人员使用和测试 NAC 的想法是，它可以防止或减轻氧化应激。通常，假定 NAC 充当 (i) 二硫键的还原剂，(ii) 活性氧的清除剂和/或 (iii) 谷胱甘肽生物合成的前体。虽然这些机制可能适用于特定情况，它们不能一概而论来解释 NAC 在大多数环境和情况下的影响。在大多数情况下，作用机制仍不清楚且未经测试。在这篇综述中，我们讨论了传统假设的有效性和新发现的作用机制的范围，即 NAC 转化为硫化氢和硫烷硫物质。过硫化物和多硫化物的抗氧化和细胞保护活性可以解释以前归因于 NAC 或 NAC 衍生的谷胱甘肽的许多作用。