Hoivik D J, Manautou J E, Tveit A, Hart S G, Khairallah E A, Cohen S D
Department of Pharmaceutical Sciences, University of Connecticut, Storrs 06269-2092.
Toxicol Appl Pharmacol. 1995 Feb;130(2):257-71. doi: 10.1006/taap.1995.1031.
Acetaminophen (APAP) is a commonly used analgesic and antipyretic agent which, in high doses, causes liver and kidney necrosis in man and animals. Damage in both target organs is greatly dependent upon biotransformation. However, in the CD1 mouse only males exhibit cytochrome P450-dependent nephrotoxicity and selective protein covalent binding. The lack of renal toxicity in female mice may reflect the androgen dependence of renal CYP2E1. To study this, female mice were pretreated with testosterone propionate and then challenged 6 days later with APAP. Groups of control males and females were similarly challenged with APAP for comparison. All groups exhibited hepatotoxicity after APAP with similar glutathione (GSH) depletion, covalent binding, centrilobular necrosis, and elevation of plasma sorbitol dehydrogenase activity. By contrast, APAP-induced nephrotoxicity occurred only in males and in the females pretreated with testosterone. No nephrotoxicity was evident in APAP-challenged control females. The selective pattern of hepatic and renal protein arylation previously reported for male mice was similarly observed in testosterone-pretreated female mice. Western blot analysis of microsomes showed that testosterone increased renal CYP2E1 levels without altering hepatic CYP2E1. Testosterone pretreatment, in vivo, also resulted in increased activation of APAP in vitro in kidney microsomes with no effect on the in vitro activation of APAP in liver microsomes. These data suggest that APAP-mediated GSH depletion, covalent binding, and toxicity in the kidneys of testosterone-pretreated females results from increased APAP activation by the testosterone-induced renal CYP2E1. This further suggests that renal, rather than hepatic, biotransformation of APAP to a toxic electrophile is central to APAP-induced nephrotoxicity in the mouse.
对乙酰氨基酚（APAP）是一种常用的止痛和解热剂，大剂量使用时会在人和动物体内导致肝和肾坏死。两个靶器官的损伤在很大程度上取决于生物转化。然而，在CD1小鼠中，只有雄性表现出细胞色素P450依赖性肾毒性和选择性蛋白质共价结合。雌性小鼠缺乏肾毒性可能反映了肾CYP2E1对雄激素的依赖性。为了研究这一点，给雌性小鼠预先注射丙酸睾酮，然后在6天后用APAP进行攻击。对照组的雄性和雌性小鼠同样用APAP进行攻击以作比较。所有组在给予APAP后均表现出肝毒性，谷胱甘肽（GSH）消耗、共价结合、小叶中心坏死以及血浆山梨醇脱氢酶活性升高的情况相似。相比之下，APAP诱导的肾毒性仅发生在雄性小鼠和预先用睾酮处理的雌性小鼠中。在接受APAP攻击的对照雌性小鼠中未发现明显的肾毒性。先前报道的雄性小鼠肝和肾蛋白质芳基化的选择性模式在预先用睾酮处理的雌性小鼠中也同样观察到。微粒体的蛋白质印迹分析表明，睾酮增加了肾CYP2E1水平，而未改变肝CYP2E1水平。在体内，睾酮预处理还导致肾微粒体中APAP的体外活化增加，而对肝微粒体中APAP的体外活化没有影响。这些数据表明，预先用睾酮处理的雌性小鼠肾脏中APAP介导的GSH消耗、共价结合和毒性是由睾酮诱导的肾CYP2E1增加的APAP活化所致。这进一步表明，APAP在小鼠中诱导肾毒性的关键在于其在肾脏而非肝脏中的生物转化为有毒的亲电试剂。
