Bourdi M, Chen W, Peter R M, Martin J L, Buters J T, Nelson S D, Pohl L R
Molecular and Cellular Toxicology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chem Res Toxicol. 1996 Oct-Nov;9(7):1159-66. doi: 10.1021/tx960083q.
Autoantibodies against specific human cytochrome P450s have been found in the sera of patients suffering from a variety of diseases, including those caused by drugs. In the cases of tienilic acid- and dihydralazine-induced hepatitis, patients have serum autoantibodies directed against cytochromes P450 2C9 and P450 1A2, respectively. In the present study, we have 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 bypass 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.
在患有包括药物所致疾病在内的多种疾病患者的血清中，已发现针对特定人类细胞色素P450的自身抗体。在替尼酸和肼屈嗪所致肝炎的病例中，患者血清中分别存在针对细胞色素P450 2C9和P450 1A2的自身抗体。在本研究中，我们发现，在56例被诊断为氟烷肝炎的患者中，有25例（45%）的自身抗体与从杆状病毒表达系统纯化的人类细胞色素P450 2E1发生反应。这些自身抗体抑制了细胞色素P450 2E1的活性，且似乎主要针对构象表位。此外，由于细胞色素P450 2E1在氧化代谢氟烷时会发生三氟乙酰化，因此细胞色素P450 2E1的共价修饰形式有可能能够避开正常情况下针对细胞色素P450 2E1的免疫耐受。类似的机制可能解释了所发现的针对氟烷活性三氟乙酰氯代谢产物其他细胞靶点的自身抗体的形成。
