title: Human anti-endoplasmic reticulum autoantibodies produced in aromatic anticonvulsant hypersensitivity reactions recognise rodent CYP3A proteins and a similarly regulated human P450 enzyme(s)
abstract: Hypersensitivity reactions to aromatic anticonvulsants are associated with anti-liver microsomal antibodies which recognise rodent proteins. The reactivity of these antibodies, the regulation of the rodent antigens and the identity of the human autoantigen have been investigated. Dexamethasone elevated markedly the levels of an immunoreactive mouse protein(s) which exhibited a Mr (53 kDa) and inducibility consistent with the major Cyp3a product. Immunoblots conducted with hepatic microsomes from control and induced rats and purified rat P450s confirmed that these antibodies also recognised constitutive (3A2) and inducible (3A1) rat CYP3A products. Negligible reactivity was observed with microsomes from human B-lymphoblastoid cell lines expressing CYP1A1, 1A2, 2A6, 2D6, 2E1, 3A4 or epoxide hydrolase. Analysis of a phenotyped human liver bank revealed that the antibodies recognised a 52.5 kDa microsomal protein which exhibited marked heterogeneity in its expression and appeared to be regulated co-ordinately with human CYP2C8 and 3A3/4. The inter-individual variation in the expression of this protein(s) and its potential induction by anticonvulsant therapy together with an inherited deficiency in drug detoxification capacity may explain predisposition to these immunoallergic reactions.
authors.affiliation: Fisons Pharmaceuticals, Department of Biochemistry, Loughborough, Leics., UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Riley
authors.forename: G
authors.initials: G
authors.lastname: Smith
authors.forename: C R
authors.initials: CR
authors.lastname: Wolf
authors.forename: V A
authors.initials: VA
authors.lastname: Cook
authors.forename: J S
authors.initials: JS
authors.lastname: Leeder
mesh_terms: D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D002220:Carbamazepine / Q000378:metabolism; D002460:Cell Line; D003429:Cross Reactions; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology*; D004342:Drug Hypersensitivity / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology*; D004828:Epilepsies, Partial / Q000188:drug therapy; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000276:immunology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000276:immunology*; D010634:Phenobarbital / Q000378:metabolism; D010672:Phenytoin / Q000009:adverse effects* / Q000378:metabolism / Q000633:toxicity; D051381:Rats
chemical_list: D000927:Anticonvulsants; D001323:Autoantibodies; D001324:Autoantigens; D007527:Isoenzymes; D002220:Carbamazepine; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D010634:Phenobarbital