Gonçalves Allan Cristian, Coelho Aline Meireles, da Cruz Castro Maria Laura, Pereira Renata Rebeca, da Silva Araújo Natalia Pereira, Ferreira Flávia Monteiro, Machado Júnior Pedro Alves, Pio Sirlaine, Vital Camilo Elber, Bezerra Frank Silva, Talvani André, de Castro Borges William, de Oliveira Emerson Cruz, Costa Daniela Caldeira
Laboratory of Metabolic Biochemistry, Institute of Exact and Biological Sciences, UFOP, Ouro Preto 35402-136, MG, Brazil.
Laboratory of Experimental Pathophysiology, Institute of Exact and Biological Sciences, UFOP, Ouro Preto 35402-136, MG, Brazil.
Toxics. 2024 Nov 27;12(12):857. doi: 10.3390/toxics12120857.
Paracetamol (APAP) overdose is the leading cause of drug-induced liver injury, leading to acute liver failure. However, the role of concurrent acute or chronic ethanol ingestion in this context requires further clarification. In this study, we investigated the effects of acute and chronic ethanol ingestion on APAP-induced hepatotoxicity. Male C57BL/6 mice were randomly allocated into four groups: control (C; water 2×/day for 7 days); APAP (single dose of APAP, 500 mg/kg); acute ethanol (AE; a single ethanol dose-10 mL/kg, and one hour later an overdose of APAP-500 mg/kg); chronic ethanol (CE; ethanol-10 mL/kg, 2×/day for 7 days; and on the last day, an overdose of APAP-500 mg/kg). The results showed that AE induced heightened liver damage, increased necrotic area, and elevated levels of ALT, AST, TBARS, and oxidized glutathione compared to the control group. The AE group exhibited diminished glutathione availability and elevated CYP2E1 levels compared to the other groups. CE maintained a hepatic profile similar to that of the control group in terms of necrosis index, ALT and AST levels, GSH/GSSG ratio, and CYP2E1 activity, along with the upregulation of gene expression of the glucuronidation enzyme compared to the APAP group. Proteomic analysis revealed that the AE protein profile closely resembled that of the APAP group, whereas the C and CE groups were clustered together. In conclusion, ethanol consumption differentially modulated APAP overdose-induced liver damage. Acute consumption exacerbated hepatotoxicity, similar to an APAP overdose alone, whereas chronic consumption appeared to mitigate this injury, at least within the parameters assessed in this study.
对乙酰氨基酚（APAP）过量服用是药物性肝损伤的主要原因，可导致急性肝衰竭。然而，在此情况下同时摄入急性或慢性乙醇的作用尚需进一步阐明。在本研究中，我们调查了急性和慢性乙醇摄入对APAP诱导的肝毒性的影响。将雄性C57BL/6小鼠随机分为四组：对照组（C；每天给予2次水，共7天）；APAP组（单次给予APAP，500 mg/kg）；急性乙醇组（AE；单次给予乙醇剂量10 mL/kg，1小时后给予过量APAP 500 mg/kg）；慢性乙醇组（CE；乙醇10 mL/kg，每天2次，共7天；在最后一天，给予过量APAP 500 mg/kg）。结果显示，与对照组相比，AE组导致更严重的肝损伤、坏死面积增加以及ALT、AST、TBARS和氧化型谷胱甘肽水平升高。与其他组相比，AE组的谷胱甘肽可用性降低且CYP2E1水平升高。在坏死指数、ALT和AST水平、GSH/GSSG比值以及CYP2E1活性方面，CE组维持了与对照组相似的肝脏状况，并且与APAP组相比，葡萄糖醛酸化酶的基因表达上调。蛋白质组学分析显示，AE组的蛋白质谱与APAP组非常相似，而C组和CE组聚集在一起。总之，乙醇摄入对APAP过量引起的肝损伤有不同的调节作用。急性摄入会加剧肝毒性，与单独的APAP过量相似，而慢性摄入似乎可以减轻这种损伤，至少在本研究评估的参数范围内如此。
