N-乙酰半胱氨酸(NAC)是一种在各种条件下使用的通用药物,但局限性和毒性尚不清楚。破译了正常小鼠腹膜内注射NAC的急性毒性和毒理学机制。雄性和雌性BALB/cByJNarl小鼠的LD50为800mg/kg和933mg/kg。研究了800mg/kgNAC(N800)的毒理机制。肝肾指标的血清生物标志物急剧增加,其次是肝微泡脂肪变性,肾小管损伤和坏死,和脾红髓萎缩和丢失。因此,N800导致小鼠死亡主要是由于急性肝脏,肾,和脾脏损伤。NAC(N275)的安全剂量(275mg/kg)通过增加谷胱甘肽水平和过氧化氢酶活性来增加肝脏的抗氧化能力。N275升高脂质转运体的肝脏基因表达,脂质合成,β-氧化,和生酮,表明脂质生产和消费之间的平衡,最后,增加ATP产量。相比之下,N800通过抑制Gclc降低谷胱甘肽水平来增加肝脏氧化应激,并降低过氧化氢酶活性。N800降低肝脏脂质转运体基因表达,脂质合成,和干扰的β氧化,导致脂质积累和Cyp2E1表达增加,最后,ATP产量下降。因此,正常个体的NAC剂量有限,尤其是通过腹膜内注射或类似方式。
N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, β-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred β-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.