Hepatic adducts, circulating antibodies, and cytokine... : Hepatology (original) (raw)

Original Articles

Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity

Aithal, Guruprasad P.1, 5; Ramsay, Lesley2; Daly, Ann K.1, 3; Sonchit, Nhareet2; Leathart, Julian B. S.1, 3; Alexander, Graeme4; Kenna, Gerald J.2, 6; Caldwell, John2, 7; Day, Christopher P.*,1,†

1 School of Clinical Medical Sciences (Hepatology), Medical School, University of Newcastle, Newcastle-upon-Tyne, United Kingdom

2 Division of Biomedical Sciences, Imperial College School of Medicine, London, United Kingdom

3 School of Clinical and Laboratory Sciences, Medical School, University of Newcastle, Newcastle-upon-Tyne, United Kingdom

4 Addenbrookes Hospital, Cambridge, United Kingdom

5 Queens Medical Centre University Hospital, Nottingham, United Kingdom

6 Astra-Zeneca plc, Alderley Park, Cheshire, United Kingdom

7 Faculty of Medicine, University of Liverpool, Liverpool L69 3GA, United Kingdom

E-mail:[email protected]

*Address reprint requests to: School of Clinical Medical Sciences (Hepatology), Medical School, University of Newcastle, Newcastle-upon-Tyne, Floor 4, William Leech Building, The Medical School, Framlington Place, Newcastle-upon-Tyne, NE24HH, United Kingdom

†fax: 44 191-222-0723

Received May 23, 2003; accepted February 13, 2004; previously published online April 26, 2004

Abstract

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 hepatotoxicity, 12 of 20 subjects on diclofenac without hepatotoxicity, and none of four healthy controls. 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. Hepatology 2004;39:1430-1440.)