MECHANISMS OF DRUG-INDUCED TOXICITIES

药物引起的毒性机制

• 批准号: 2576755
• 负责人: Lance R Pohl
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2576755
• 关键词: autoantibody; cytochrome P450; drug adverse effect; drug metabolism; halothane; hepatitis; hepatotoxin; human tissue; inhalation anesthesia; laboratory rat; liver toxic disorder; nonsteroidal antiinflammatory agent

In our studies this year of the mechanism of hepatitis caused by inhalation anesthetics, it was found that 25 of 56 (45%) patients diagnosed with halothane hepatitis have autoantibodies that react with human cytochrome P450 2E1 that was purified from a baculovirus expression system. The autoantibodies inhibited the activity of cytochrome P450 2E1 and appeared to be directed against mainly conformational epitopes. In addition because cytochrome P450 2E1 became trifluoroacetylated when it oxidatively metabolized halothane, it is possible that the covalently altered form of cytochrome P450 2E1 may be able to by-pass the immunologic tolerance that normally exists against cytochrome P450 2E1. A similar mechanism may explain the formation of autoantibodies that have been found against other cellular targets of the reactive trifluoroacetyl chloride metabolite of halothane. We have continued to study the protein adducts of the nonsteroidal antiinflammatory drug diclofenac, in an effort to determine how this widely used drug causes hepatitis. The 50 kDa microsomal covalent adduct of diclofenac found in rat liver was identified last year as male specific cytochrome P4502C11. This year we have found that this enzyme catalyzes its own covalent alteration and inactivation, when it metabolizes diclofenac into a reactive metabolite. It has also been discovered that diclofenac is metabolically activated into a reactive metabolite by another specific form of cytochrome P450 in human liver. Moreover, only a small percent of individuals appear to have sufficient levels of this enzyme in their liver to catalyze the formation of protein adducts of diclofenac, which may be responsible for causing diclofenac hepatotoxicity. These findings suggest that one factor that may predispose a patient to develop diclofenac hepatitis is the expression of high levels of liver cytochrome P450 that metabolically activates this drug.

在我们今年的研究中， 吸入麻醉剂，发现56例患者中有25例（45%） 诊断为氟烷肝炎的患者有自身抗体， 从杆状病毒表达纯化的人细胞色素P450 2E1 系统 自身抗体抑制细胞色素P450 2E1的活性 并且似乎主要针对构象表位。 在 添加，因为细胞色素P450 2E1成为三氟乙酰化时， 氧化代谢的氟烷，有可能共价 细胞色素P450 2E1的改变形式可能能够绕过细胞色素P450 2E1。 免疫耐受性，通常存在对细胞色素P450 2E1。 类似的机制可以解释自身抗体的形成， 被发现对其他细胞目标的反应性三氟乙酰 氟烷的氯化物代谢物。 我们继续研究这种蛋白质 非甾体类药物双氯芬酸的加合物， 努力确定这种广泛使用的药物如何引起肝炎。 的50 在大鼠肝脏中发现的双氯芬酸kDa微粒体共价加合物， 去年被鉴定为男性特异性细胞色素P4502C11。 今年我们 已经发现这种酶催化其自身的共价改变， 失活，将双氯芬酸代谢为活性代谢物。 还发现双氯芬酸具有代谢活化作用， 转化为另一种特定形式的细胞色素P450的活性代谢物 在人类肝脏中。 此外，只有一小部分人似乎 在他们的肝脏中有足够的这种酶来催化 形成双氯芬酸的蛋白加合物，这可能是导致 引起双氯芬酸肝毒性。 这些发现表明， 可能使患者易患双氯芬酸肝炎的因素是 高水平的肝细胞色素P450的表达， 激活这种药物。