Diclofenac is a nonsteroidal anti-inflammatory drug that causes rare but serious hepatotoxicity, the mechanism of which is unclear. The purpose of the present study was to explore the potential role played by the immune processes. Antibodies to diclofenac metabolite-modified liver protein adducts were detected in the sera of seven out of seven patients with diclofenac-induced hepato-toxicity, 12 of 20 subjects on diclofenac without hepatotoxicity, and none of four healthy con-trols. The antibodies recognized adducts expressed in livers from rats treated with multiple doses of diclofenac, but not in those given single doses. In addition, several potential diclofenac adducts were identified in the liver of a patient with diclofenac-induced hepatic failure, but not from a normal human donor liver, by immunoblotting with an adduct-selective rabbit antiserum. To determine whether or not polymorphisms in genes encoding cytokine-related proteins influence susceptibility to hepatotoxicity, genotyping for the polymorphisms -627 in the interleukin (IL)-10 gene, -590 in the IL-4 gene, and codon 551 in the IL-4 receptor (IL-4R) were performed on DNA from 24 patients on diclofenac with hepatotoxicity, 48 subjects on diclofenac without hepatotoxicity, and healthy controls. The frequencies of the variant alleles for IL-10 and IL-4 were higher in patients (OR [odds ratio]: 2.8 for IL-10; 2.6 for IL-4; 5.3 for IL-10 ؉ IL-4) compared with healthy controls and subjects on diclofenac without hepatotoxicity (OR: 2.8 for IL-10; 1.2 for IL-4; 5.0 for IL-10 ؉ IL-4). In conclusion, the observed polymorphisms, resulting in low IL-10 and high IL-4 gene transcription, could favor a T helper (Th)-2 mediated antibody response to neoantigenic stimulation associated with disease susceptibility. Supplementary ma-terial for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/ jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;39:1430 –1440.) D iclofenac is a widely used nonsteroidal anti-in-flammatory drug that can cause rare but poten-tially serious hepatotoxicity. Approximately 3.6 per 100,000 users of diclofenac develop severe liver in-jury 1 with an 8% case fatality rate. 2 Because of its com-mon use, diclofenac hepatotoxicity has been one of the most common causes of hepatic adverse drug reactions, with 180 confirmed cases reported to the U.S. Food and Drug Administration during the first 3 years of market-ing. 2 Although the precise mechanism of diclofenac-in-duced hepatotoxicity is unknown, both metabolic 2 and immunological 3 mechanisms have been thought to con-tribute to liver injury. A common mechanism that may underlie either immunomediated liver injury or meta-bolic idiosyncrasy is the formation of drug-modified pro-tein adducts. 4 For several drugs, such as halothane and dihydralazine, antibodies directed against specific hepato-cellular proteins have been identified. 5 In each of these cases, covalent adducts of reactive drug metabolites and hepatocellular proteins have been implicated in triggering Abbreviations: IL, interleukin; IL-4R, interleukin-4 receptor; OR, odds ratio; Th, T helper; KLH, keyhole limpet hemocyanin; Ig, immunoglobulin; IP, intra-peritoneal; RSA, rabbit serum albumin; TBS, tris-buffered saline; GSA, goat serum albumin.
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