Autoantibodies against cytochrome P450s in sera of children treated with immunosuppressive drugs.
Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti-graft rejection and autoimmune disease therapy, is limited by their hepato- and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti-CYP reactivity in 16% of children on CyA for anti-graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8.5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti-cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.
Lytton
S D
SD
Division of Molecular Toxicology, Institute for Environmental Medicine, Karolinska Institute, and Department of Paediatrics, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden. lyttons@intra.nei.nih.gov
Berg
U
U
Nemeth
A
A
Ingelman-Sundberg
M
M
D000293:Adolescent; D000328:Adult; D000918:Antibody Specificity; D001189:Aryl Hydrocarbon Hydroxylases; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001379:Azathioprine / Q000008:administration & dosage / Q000627:therapeutic use; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019388:Cytochrome P-450 CYP1A2 / Q000276:immunology; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D004359:Drug Therapy, Combination; D000939:Epitopes / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007223:Infant; D007527:Isoenzymes / Q000276:immunology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000276:immunology; D011183:Postoperative Complications / Q000139:chemically induced; D011241:Prednisone / Q000008:administration & dosage / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000276:immunology; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human; D001379:Azathioprine; D011241:Prednisone; D016559:Tacrolimus