Immunotoxicology and expression of human cytochrome P450 in microorganisms.
Drug-induced hepatitis can be caused by an abnormal immunological response. In the case of tienilic acid- and dihydralazine-induced hepatitis, we postulated a scheme in which a P450 produced a reactive metabolite (step 1); this reactive metabolite bound to the P450 producing it (step 2) leading to a neoantigen triggering the immune response (step 3); the autoantibodies produced during the immune response recognized the P450 producing the reactive metabolite (step 4). The use of microorganisms (yeast or bacteria) expressing cloned human P450 helped in proving some steps of this postulated scheme, particularly steps 1 and 4.
Beaune
P
P
Inserm U75, CHU Necker, Laboratoire de Biochimie, Paris, France.
Bourdi
M
M
Belloc
C
C
Gautier
J C
JC
Guengerich
F P
FP
Valadon
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001419:Bacteria / Q000235:genetics; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000276:immunology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004078:Dihydralazine / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D011817:Rabbits; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013989:Ticrynafen / Q000378:metabolism / Q000633:toxicity
D001323:Autoantibodies; D003577:Cytochrome P-450 Enzyme System; D013989:Ticrynafen; D004078:Dihydralazine