Expression and inducibility of antigens in severe combined immunodeficient mice recognized by human anti-P450 antibodies.
Engrafting components of human immune systems in severe combined immunodeficient (SCID) mice has been utilized to investigate the pathogenesis of several human autoimmune diseases and may provide a model for studying idiosyncratic drug toxicity. The purpose of this investigation was to examine in SCID mice the tissue distribution and inducibility of antigens recognized by anti-cytochrome P450 (CYP) antibodies in sera from patients with hypersensitivity reactions to the aromatic anticonvulsants phenytoin, phenobarbital, and carbamazepine. Microsomal proteins were prepared from liver, skin, kidney, intestine, and lung of SCID mice pretreated with vehicle (50% propylene glycol/DMSO), phenytoin, carbamazepine, phenobarbital, or dexamethasone. Proteins immunoreactive with anti-CYP2C and anti-CYP3A antisera were detected in all organs examined. Antibodies in patient sera recognized a 53-kDa hepatic microsomal protein that was expressed to a limited extent in vehicle-pretreated microsomes, but which was induced by dexamethasone, phenytoin, and phenobarbital, but not carbamazepine. This antigen was very similar to a 52.5-kDa protein immunoreactive with anti-CYP3A polyclonal antibody. The expression and inducibility of the 53-kDa antigen correlated significantly with testosterone 6 beta-, 2 beta-, and 15 beta-hydroxylation and erythromycin N-demethylase activity, all markers of CYP3A activity, and is tentatively identified as CYP3A11. No immunoreactivity was observed in murine extrahepatic organs including skin, kidney, intestine, and lung. Therefore, further development of the SCID mouse model may require xenotransplantation of human target organs like skin together with transfer of patient immune systems to reproduce the serological and pathological features of human anticonvulsant hypersensitivity reactions.
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000918:Antibody Specificity; D000927:Anticonvulsants / Q000009:adverse effects / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000096:biosynthesis* / Q000276:immunology; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D003600:Cytosol / Q000276:immunology; D004342:Drug Hypersensitivity / Q000209:etiology / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000276:immunology; D014018:Tissue Distribution / Q000276:immunology
D000906:Antibodies; D000927:Anticonvulsants; D000941:Antigens; D003577:Cytochrome P-450 Enzyme System