Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
Environ Toxicol. 2011 Jun;26(3):250-9. doi: 10.1002/tox.20551.
Acetaminophen (AP) is a widely used, cheap, and over-the-counter nonsteroidal anti-inflammatory drug. Its toxicity depends on the cytochrome P-450 (CYP)-mediated oxidation to the toxic metabolite N-acetyl-p-benzoquinoneimine. On the other hand, arsenic, a global groundwater and environmental contaminant of major public health concern, decreases hepatic CYP content and its dependent monoxygenase activities. We hypothesized that arsenic exposure would reduce the AP toxicity. Our aim was to evaluate the effects of repeated preexposure or coexposure to arsenic on the oxidative stress induced by a single or repeated oral administration of AP in rat kidney and its possible relationship with the effects of arsenic on certain antioxidants. Rats were exposed to arsenic through drinking water at 25 ppm for 28 days. The dosages of AP used for a single administration after arsenic preexposure for 28 days were 420 and 1000 mg kg(-1) , while for daily concurrent administration with arsenic for 28 days were 105 and 420 mg kg(-1) body weight. AP increased lipid peroxidation (LPO) in rat kidney where its acute administration caused more LPO than its subacute dosing. Repeated arsenic exposure differentially altered the AP-induced LPO. Arsenic preexposure antagonized LPO induced by the acute AP administration; in contrast, arsenic coexposure aggravated the repeated dose (AP)-mediated LPO. Arsenic-mediated alterations in renal sensitivity to LPO did not appear to be linked to the antioxidants such as reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase; nor could it be related to glutathione-S-transferase activity. The results indicated that repeated arsenic preexposure decreased susceptibility of rat kidney to acute AP-mediated oxidative stress; on the contrary, its coexposure rendered the rat kidney more vulnerable to oxidative stress induced by the repeated dosing of AP.
对乙酰氨基酚（AP）是一种广泛使用的廉价非甾体抗炎药。其毒性取决于细胞色素 P-450（CYP）介导的氧化作用，生成有毒的代谢物 N-乙酰苯醌亚胺。另一方面，砷是一种全球地下水和环境污染物，主要对公共健康构成重大关切，会降低肝 CYP 含量及其依赖的单加氧酶活性。我们假设砷暴露会降低 AP 的毒性。我们的目的是评估重复预暴露或共暴露于砷对单次或重复口服 AP 诱导的大鼠肾脏氧化应激的影响，以及其与砷对某些抗氧化剂的影响的可能关系。大鼠通过饮用水暴露于 25ppm 的砷 28 天。在砷预暴露 28 天后单次给予 AP 的剂量分别为 420 和 1000mg/kg，而与砷同时每日给予的剂量分别为 105 和 420mg/kg 体重。AP 增加了大鼠肾脏的脂质过氧化（LPO），其急性给药比亚急性给药引起更多的 LPO。重复砷暴露改变了 AP 诱导的 LPO。砷预暴露拮抗了急性 AP 给药引起的 LPO；相反，砷共暴露加重了重复剂量（AP）介导的 LPO。砷对肾脏对 LPO 敏感性的改变似乎与抗氧化剂如还原型谷胱甘肽、超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶和谷胱甘肽还原酶无关；也与谷胱甘肽-S-转移酶活性无关。结果表明，重复砷预暴露降低了大鼠肾脏对急性 AP 介导的氧化应激的敏感性；相反，共暴露使大鼠肾脏对 AP 重复剂量诱导的氧化应激更加敏感。
