Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes

Gastroenterology. 2007 Jan;132(1):272-81. doi: 10.1053/j.gastro.2006.11.023. Epub 2006 Nov 17.

Abstract

Background & aims: Diclofenac is a widely used nonsteroidal anti-inflammatory drug and is among the most common drugs causing idiosyncratic hepatotoxicity in several recent series with up to 20% mortality in jaundiced subjects. We hypothesized that susceptibility to hepatotoxicity would be associated with genetic polymorphisms in the genes encoding the enzymes UGT2B7 and CYP2C8, which determine the formation of reactive diclofenac metabolites and in ABCC2 encoding the transporter MRP2 contributing to the biliary excretion of the reactive metabolite.

Methods: Twenty-four patients (19 female) aged 24-70 (mean, 50.8) years who had suffered diclofenac hepatotoxicity, 48 subjects (35 female) aged 22-77 (mean, 52) years who were taking diclofenac for 0.3-20 (mean, 4) years without developing hepatotoxicity (hospital controls), and 112 healthy controls were investigated. Genotyping for several polymorphisms in the genes encoding UGT2B7, CYP2C8, and ABCC2 was performed and haplotypes assigned.

Results: The UGT2B7*2 allele was more common in diclofenac hepatotoxicity patients compared with hospital controls (odds ratio [OR], 8.5, P = .03) and healthy controls (OR, 7.7, P = .03). The ABCC2 C-24T variant was more common in hepatotoxicity patients compared with hospital (OR, 5.0, P = .005) and healthy controls OR: 6.3, P = .0002). Haplotype distributions for CYP2C8 were different in patients compared with hospital controls (P = .04).

Conclusions: Allelic variants of UGT2B7, CYP2C8, and ABCC2, which may predispose to the formation and accumulation of reactive diclofenac metabolites are associated with diclofenac hepatotoxicity. Increased level of reactive metabolites may lead to higher levels of protein-diclofenac adducts and subsequently hepatotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Chemical and Drug Induced Liver Injury / genetics*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Cytochrome P-450 CYP2C8
  • Diclofenac / adverse effects*
  • Diclofenac / pharmacokinetics
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Glucuronosyltransferase / genetics*
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics*
  • Phenotype
  • Polymorphism, Genetic

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Diclofenac
  • multidrug resistance-associated protein 2
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • UGT2B7 protein, human
  • Glucuronosyltransferase