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

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 (

Acute liver failure in children: The first 348 patients in the pediatric acute liver failure study group

“…(27)In addition, polymorphisms of genes associated with drug detoxification or cytokine expressions may enhance a patient's susceptibility to liver injury. (28,29) Patient outcome was influenced by a number of factors including age, diagnosis, the degree of HE, and severity of the coagulopathy. The risk of death or liver transplant was highest among children <3 years of age.…”

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

“…Moreover, DCLF is normally prescribed to patients with inflammatory conditions, in which inflammatory mediators are usually present. The role of inflammatory stress in DCLF hepatotoxicity is further suggested by the clinical findings that IL-4 and IL-10 polymorphisms have been found in human patients who developed hepatotoxicity after DCLF treatment (Aithal et al, 2004). These polymorphisms would lead to less IL-10 and more IL-4 production.…”

“…Because DCLF is normally given orally to human patients, this raises a question about the likelihood that immunoallergic reactions contribute to DCLF-induced IADRs. DCLF autoantibodies have been found in human patients, but their relevance to idiosyncratic hepatotoxicity is unknown (Aithal et al, 2004). Thus, the lack of a demonstrable connection between an immunoallergic response to DCLF and overt hepatotoxicity raises a question as to whether DCLF IADRs occur by this mechanism.…”

An Improved Synthesis of 4'-Hydroxydiclofenac

“…4 Numerous reports related to the diclofenac metabolism and its toxicological consequences have indicated that metabolites of 1 possess a different activity from 1, resulting in various side effects or toxicities, and that hepatotoxicity is mainly induced by metabolites of 1 rather than by 1 itself. [5][6] In addition, the environmental effects of these hydroxyl metabolites to non-target organisms have recently become of great concern due to their toxicities. 7 In connection with our ongoing project investigating the environmental fate and ecotoxicological effects of 1 and its metabolites on the environment, we need to synthesize substantial quantities of 2.…”