Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis.
Sera from patients with dihydralazine-induced hepatitis were shown to contain anti-liver microsomal autoantibodies (anti-LM) by indirect immunofluorescence. These anti-LM antibodies were different from anti-liver/kidney microsomes (anti-LKM) 1 or 2 autoantibodies which have been previously described. Sera recognized a single 53,000 = Mr polypeptide in human liver microsomes as judged by immunoblotting, and the target antigen was identified as cytochrome P-450IA2 (P-450IA2) by (a) comparison of immunoblotting patterns with anti-human P-450IA2 and anti-rat P-450IA2 and with five anti-LM sera, and (b) specific immunoinhibition of microsomal ethoxyresorufin and phenacetin O-deethylation activities (both P-450IA2 supported reactions) by anti-LM antibodies. Finally, purified human P-450IA2 was recognized by these anti-LM sera. The anti-LM antibodies are specific for the disease because none of the other antisera tested behaved in the same manner as anti-LM, even those from patients treated with dihydralazine and without hepatic disease. A possible role of P-450IA2 in the metabolism of dihydralazine was suggested by competitive inhibition of ethoxyresorufin-O-deethylase observed in microsomal incubations. Thus, a new example is presented in which a cytochrome P-450 may be a target for autoantibodies in drug-induced hepatitis.
Bourdi
M
M
Institut National de la Santé et de la Recherche Médicale U 75, CHU Necker-Enfants-Malades, Paris, France.
Larrey
D
D
Nataf
J
J
Bernuau
J
J
Pessayre
D
D
Iwasaki
M
M
Guengerich
F P
FP
Beaune
P H
PH
D001323:Autoantibodies / Q000276:immunology*; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000276:immunology*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology* / Q000378:metabolism; D004078:Dihydralazine; D004721:Endoplasmic Reticulum / Q000276:immunology*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism
D001323:Autoantibodies; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D004078:Dihydralazine