Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis

Grabar, Petra Bohanec; Rozman, B; Logar, D; Praprotnik, Sonja; Dolžan, Vita

doi:10.1136/ard.2008.099093

Cited by 37 publications

(21 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results of our study are in contrast to previous studies of leflunomide toxicity that have reported no relationship with CYP2C19 genotype, but did demonstrate an association with SNPs in CYP1A2 and DHODH [6,7]. There are a number of important differences in both study design and the participants included in our study compared to these previous reports (which were presumably performed on the same patient population) which may account for these discrepancies.…”

Section: Discussioncontrasting

confidence: 99%

“…The conversion of leflunomide to teriflunomide is mediated by CYP1A2 (in addition to CYP2C19) [2], and the immunosuppressive properties are mediated by inhibition of DHODH [8], but there is currently no biologically plausible explanation for the proposed associations of CYP1A2 and DHODH genotype and leflunomide toxicity [6,7]. The CYP1A2*1F allele occurs in the promoter region of the CYP1A2 gene (in intron 1), and is thought to be important in induction of enzymatic activity in smokers (smokers who carried one or two C residues had higher enzyme activity compared to those who had the AA genotype), but it does not have an effect on enzymatic activity in non-smokers [18].…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms were chosen based on the potential importance of proteins for which they encode on steady state teriflunomide blood levels via an effect on leflunomide metabolism ( CYP2C19*2 ( CYP2C19 681G>A, rs4244285) and CYP2C19*17 ( CYP2C19 , 608C>T, rs12248560) [2,3]) or biliary secretion of teriflunomide ( ABCG2 421C>A, rs2231142) [4,5]). Polymorphisms that had been linked to leflunomide toxicity ( CYP1A2*1F, (CYP1A2 163C>A, rs762551) and DHODH ( DHODH 19C>A, rs3213422) [3,6,7]) were also studied. DHODH was also of interest because inhibition of the encoded protein dihydro-orotate dehydrogenase (DHODH) by teriflunomide appears to be the principal basis of the anti-inflammatory/immunosuppressive effects of leflunomide [8].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

et al. 2012

View full text Add to dashboard Cite

IntroductionRational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.MethodsThis retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.ResultsThirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.ConclusionsCYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Each of the amino acid residues affected by a DHODH mutation is highly conserved among homologues studied to date (Supplementary Figure 1). A single validated nonsynonymous polymorphism in human DHODH has been studied by Grabar et al19 This polymorphism causes a lysine to glutamine substitution in the relatively diverse N-terminal extension of dihydroorotate dehydrogenase that is responsible for the association of the enzyme with the inner mitochondrial membrane.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing identifies the cause of a mendelian disorder

et al. 2009

View full text Add to dashboard Cite

We demonstrate the first successful application of exome sequencing to discover the gene for a rare, Mendelian disorder of unknown cause, Miller syndrome (OMIM %263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40X, and sufficient depth to call variants at ~97% of each targeted exome. Filtering against public SNP databases and a small number of HapMap exomes for genes with two novel variants in each of the four cases identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated, affected individuals is a powerful, efficient strategy for identifying the genes underlying rare Mendelian disorders and will likely transform the genetic analysis of monogenic traits.

show abstract

“…One mechanism of LEF action in suppressing inflammation is based on its inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme responsible for de novo synthesis of pyrimidine nucleotides. Moreover, polymorphism in the DHODH gene may be associated with LEF treatment response and toxicity [5, 6]. Upon absorption, LEF is quickly metabolized to malononitrilamide (MNA or A77 1726) as the active therapeutic agent.…”

Section: Introductionmentioning

confidence: 99%

Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide

Dziedziejko

Kurzawski

Safranow

et al. 2011

Eur J Clin Pharmacol

View full text Add to dashboard Cite

PurposeLeflunomide (LEF) is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA) and the action of which may be modified by sex hormones. The aim of this study was to examine the association between CAG repeat polymorphism in the androgen receptor (AR) gene and the response to treatment with LEF in women with RA.MethodsWe studied 114 women diagnosed with RA and treated with LEF (20 mg daily). Follow-up was 12 months. CAG repeat polymorphism was determined using polymerase chain reaction (PCR) and subsequent fragment analysis by capillary electrophoresis.ResultsAnalysis revealed no statistically significant associations between CAG repeat polymorphism in the AR gene and improvement of disease activity parameters: erythrocyte sedimentation rate, serum C-reactive protein, patient’s global assessment of disease activity on a visual analog scale (VAS), disease activity score of 28 joints (DAS28), and swollen and tender joint count.ConclusionOur results suggest no correlation between CAG repeat polymorphism in the AR gene and response to treatment with LEF in women with RA.

show abstract

Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis

Cited by 37 publications

References 7 publications

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

Exome sequencing identifies the cause of a mendelian disorder

Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide

Contact Info

Product

Resources

About