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 immun odeficient (SCID) mice has been utilized to investigate the pathogenes is of several human autoimmune diseases and may provide a model for st udying idiosyncratic drug toxicity, The purpose of this investigation was to examine in SCID mice the tissue distribution and inducibility o f antigens recognized by anti-cytochrome P450 (CYP) antibodies in sera from patients with hypersensitivity reactions to the aromatic anticon vulsants phenytoin, phenobarbital, and carbamazepine. Microsomal prote ins were prepared from liver, skin, kidney, intestine, and lung of SCI D mice pretreated with vehicle (50% propylene glycol/DMSO), phenytoin, carbamazepine, phenobarbital, or dexamethasone, Proteins immunoreacti ve with anti-CYP2C and anti-CYP3A antisera were detected in all organs examined, Antibodies in patient sera recognized a 53-kDa hepatic micr osomal protein that was expressed to a limited extent in vehicle-pretr eated microsomes, but which was induced by dexamethasone, phenytoin, a nd phenobarbital, but not carbamazepine, This antigen was very similar to a 52.5-kDa protein immunoreactive with anti-CYP3A polyclonal antib ody. The expression and inducibility of the 53-kDa antigen correlated significantly with testosterone 6 beta-, 2 beta-, and 15 beta-hydroxyl ation acid erythromycin N-demethylase activity, all markers of CYP3A a ctivity, and is tentatively identified as CYP3A11, No immunoreactivity was observed in murine extrahepatic organs including skin, kidney, in testine, and lung. Therefore, further development of the SCID mouse mo del may require xenotransplantation of human target organs like skin t ogether with transfer of patient immune systems to reproduce the serol ogical and pathological features of human anticonvulsant hypersensitiv ity reactions, (C) 1995 Academic Press, Inc.