Antigenic targets in tienilic acid hepatitis - Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera

被引：53

作者：

Robin, MA

Maratrat, M

LeRoy, M

LeBreton, FP

Bonierbale, E

Dansette, P

Ballet, F

Mansuy, D

Pessayre, D

机构：

[1] HOP BEAUJON,INSERM,U24,F-92118 CLICHY,FRANCE

[2] HOP BEAUJON,CTR RECH PHYSIOPATHOL HEPAT ASSOC CLAUDE BERNARD,F-92118 CLICHY,FRANCE

[3] RHONE POULENC RORER,DEPT SECUR MEDICAMENT,F-94140 ALFORTVILLE,FRANCE

[4] CNRS,URA 400,F-75005 PARIS,FRANCE

来源：

JOURNAL OF CLINICAL INVESTIGATION | 1996年 / 98卷 / 06期

关键词：

cell traffic; vesicular transport; microtubules; neoantigen; immunoallergic hepatitis;

D O I：

10.1172/JCI118936

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Patients with tienilic acid hepatitis exhibit autoantibodies that recognize unalkylated cytochrome P450 2C9 in humans but recognize 2C11 in rats. Our aim was to determine whether the immune reaction is also directed against neoantigens. Rats were treated with tienilic acid and hepatocytes were isolated. Immunoprecipitation, immunoblotting, and now cytometry experiments were performed with an anti-tienilic acid or an anti-cytochrome P450 2C11 antibody. Cytochrome P450 2C11 was the main microsomal or plasma membrane protein that was alkylated by tienilic acid. Inhibitors of vesicular transport decreased now cytometric recognition of both unalkylated and tienilic acid-alkylated cytochrome P450 2C11 on the plasma membrane of cultured hepatocytes. Tienilic acid hepatitis sera that were preadsorbed on microsomes from untreated rats (to remove autoantibodies), poorly recognized untreated hepatocytes in flow cytometry experiments, but better recognized tienilic acid-treated hepatocytes. This recognition was decreased by adsorption with tienilic acid or by preexposure to the anti-tienilic acid or the anti-cytochrome P450 2C11 antibody. We conclude that cytochrome P450 2C11 is alkylated by tienilic acid and follows a vesicular route to the plasma membrane. Tienilic acid hepatitis sera contain antibodies against this tienilic acid adduct, in addition to the previously described anti-cytochrome P450 autoantibodies.

引用

页码：1471 / 1480

页数：10

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