Anti-cytochrome P450 autoantibodies in drug-induced disease.
Drugs may induce hepatitis through immune mechanisms. In this review we have used the examples of 2 drugs to elucidate the first steps leading to the triggering of such disease, namely tienilic acid (TA) and dihydralazine (DH). These drugs are transformed into reactive metabolite(s) by cytochrome P450 (2C9 for TA and 1A2 for DH) (step 1). The reactive metabolites produced are very short-lived and bind directly to the enzymes which generated them (step 2). A neoantigen is thus formed which triggers an immune response (step 3), characterized by the presence of autoantibodies in the patient's serum (step 4). The autoantibodies are directed against the cytochrome P450 which generated the metabolite(s). Although the process by which TA and DH induce-hepatitis has been elucidated, further studies are necessary to generalize this mechanism. In addition, an animal model will also be useful to fully understand the immune mechanism of this type of disease.
Beaune
P H
PH
INSERM U 75, Université René Descartes, Paris, France. pbeaune@citi2.fr
Lecoeur
S
S
Bourdi
M
M
Gauffre
A
A
Belloc
C
C
Dansette
P
P
Mansuy
D
D
D001323:Autoantibodies / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D004078:Dihydralazine / Q000009:adverse effects*; D006801:Humans; D013989:Ticrynafen / Q000009:adverse effects*
D001323:Autoantibodies; D003577:Cytochrome P-450 Enzyme System; D013989:Ticrynafen; D004078:Dihydralazine