Anti-liver microsomes autoantibodies and dihydralazine-induced hepatitis: specificity of autoantibodies and inductive capacity of the drug.
Anti-liver microsomes (anti-LM) autoantibodies in patients with dihydralazine-induced hepatitis were found to react specifically with cytochrome P4501A2 (P4501A2) but not with P4501A1 expressed in yeast and bacteria. These results were confirmed by immunoinhibition of methoxyresorufin-O-demethylase activity (supported by the P4501A subfamily); anti-LM antibodies more strongly inhibited this activity in yeast expressing P4501A2 than in yeast expressing P4501A1. Anti-LM were shown to be specific to the disease; in three cases, these autoantibodies were present at high titers during disease, whereas the titers decreased upon recovery and became undetectable a few months after recovery. Thus, there exists a time-dependent relationship between the disease and the autoantibodies, which does not prove that the autoantibodies are causative of the hepatitis; they might only be a marker. The inductive capacity of dihydralazine toward P450 was also studied. In rats treated in vivo and in human hepatocytes treated in vitro with dihydralazine, a 2-fold increase in P4501A2- and P4501A-supported monooxygenase activities was found. The levels of the other P450 isoforms tested were unchanged during treatment, both in vivo in rats and in vitro in cultures of human hepatocytes. In human hepatocytes, dihydralazine produced a dose-dependent increase in the level of P4501A up to 0.1 mM; induction of P4501A was less strong at 0.2 mM and disappeared at 0.5 mM. The same treatment did not change the level of P4503A4, taken as control. The strong heterogeneity in the expression of P4501A enzymes in human liver and the capacity of these enzymes for induction by dihydralazine and by other compounds might be predisposing factors in this autoimmune disease.
Bourdi
M
M
Institut National de la Santé et de la Recherche Médicale Unité 75, Centre Hospitalo-Universitaire Necker-Enfants-Malades, Paris, France.
Gautier
J C
JC
Mircheva
J
J
Larrey
D
D
Guillouzo
A
A
Andre
C
C
Belloc
C
C
Beaune
P H
PH
D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004078:Dihydralazine / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D010088:Oxidoreductases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001323:Autoantibodies; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D004078:Dihydralazine