Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes.
OBJECTIVE
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.
Daly
Ann K
AK
School of Clinical & Laboratory Sciences, University of Newcastle Medical School, Framlington Place, Newcastle upon Tyne, UK. A.K.Daly@ncl.ac.uk
Aithal
Guruprasad P
GP
Leathart
Julian B S
JB
Swainsbury
Richard A
RA
Dang
Tarana Singh
TS
Day
Christopher P
CP
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D004008:Diclofenac / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001189:Aryl Hydrocarbon Hydroxylases; D065727:Cytochrome P-450 CYP2C8; D004008:Diclofenac; D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C450259:CYP2C8 protein, human; C491474:UGT2B7 protein, human