Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35% reduced activity in the 4′-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines.

Original languageEnglish
Pages (from-to)70-78
Number of pages9
JournalToxicology Letters
Volume284
Issue number1 March
Early online date2 Dec 2017
DOIs
Publication statusPublished - 1 Mar 2018

Fingerprint

Diclofenac
Polymorphism
Metabolism
Liver
Chemical and Drug Induced Liver Injury
Alleles
Enzyme kinetics
Hydroxylation
Proteins
Gene encoding
Uridine Diphosphate
Enzymes
Transferases
Metabolites
Cytochrome P-450 CYP2C8
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Genotype
Association reactions
Antibodies

Keywords

  • Acyl glucuronides
  • Bioactivation
  • Diclofenac
  • Drug-induced liver injury
  • Genetic polymorphism

Cite this

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title = "Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism",
abstract = "The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35{\%} reduced activity in the 4′-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines.",
keywords = "Acyl glucuronides, Bioactivation, Diclofenac, Drug-induced liver injury, Genetic polymorphism",
author = "Lazarska, {Katarzyna E.} and Dekker, {Stefan J.} and Vermeulen, {Nico P.E.} and Commandeur, {Jan N.M.}",
note = "Copyright {\circledC} 2017 The Author(s). Published by Elsevier B.V. All rights reserved.",
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doi = "10.1016/j.toxlet.2017.11.038",
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Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism. / Lazarska, Katarzyna E.; Dekker, Stefan J.; Vermeulen, Nico P.E.; Commandeur, Jan N.M.

In: Toxicology Letters, Vol. 284, No. 1 March, 01.03.2018, p. 70-78.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism

AU - Lazarska, Katarzyna E.

AU - Dekker, Stefan J.

AU - Vermeulen, Nico P.E.

AU - Commandeur, Jan N.M.

N1 - Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35% reduced activity in the 4′-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines.

AB - The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35% reduced activity in the 4′-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines.

KW - Acyl glucuronides

KW - Bioactivation

KW - Diclofenac

KW - Drug-induced liver injury

KW - Genetic polymorphism

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