CYP2D6 polymorphism in systemic lupus erythematosus patients

Kortunay, Selim; Bozkurt, Atilla; Bathum, Lise; Ne, Basci; Çalgünerı, Meral; Brøsen, Kim; So, Kayaalp

doi:10.1007/s002280050587

Cited by 12 publications

(15 citation statements)

References 15 publications

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“…The practice of administration of debrisoquine to human subjects has all but vanished, being replaced by highly accurate phenotype forecasting using molecular genotyping methods (McElroy et al, 2000). However, there are a handful of recent studies that rely on debrisoquine administration to determine CYP2D6 phenotype (Kortunay et al, 1999;Cerqueira et al, 2000;Haffen et al, 2000). Until the development of polymerase chain reaction-based CYP2D6 genotyping methodologies (Heim and Meyer, 1990), determination of CYP2D6 phenotype largely relied on the premise that the drugs used to uncover phenotype were specific substrates for CYP2D6.…”

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confidence: 99%

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Granvil

Krausz²,

Gelboin³

et al. 2002

J Pharmacol Exp Ther

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A panel of 15 recombinant cytochromes P450 expressed in human B-lymphoblastoid cells was used to study debrisoquine 4-hydroxylation. Both CYP2D6 and CYP1A1 carried out the reaction. The apparent K m (micromolar) and V max (picomoles per minute per picomole of P450) for CYP2D6 were 12.1 and 18.2 and for CYP1A1 were 23.1 and 15.2, respectively. CYP1A1 debrisoquine 4-hydroxylase was inhibited by the CYP1A1 inhibitor ␣-naphthoflavone and the CYP1A1 substrate 7-ethoxyresorufin. Additionally and surprisingly, this reaction was also inhibited by quinidine and quinine, with respective IC 50 values of 1.38 Ϯ 0.10 and 3.31 Ϯ 0.14 M, compared with those for CYP2D6 debrisoquine 4-hydroxylase of 0.018 Ϯ 0.05 and 3.75 Ϯ 2.07 M, respectively. Anti-CYP1A1 monoclonal antibody (mAb) 1-7-1 abolished CYP1A1 debrisoquine hydroxylase and anti-CYP2D6 mAb 50-1-3 eradicated CYP2D6 debrisoquine 4-hydroxylase. Three further CYP2D6-specific reactions were tested: dextromethorphan O-demethylation, bufuralol 1Ј-hydroxylation, and sparteine dehydrogenation. The CYP2D6 specificity, judged by the CYP2D6/CYP1A1 activity ratios was 18.5, 7.0, 6.0, and 1.6 for dextromethorphan, bufuralol, sparteine, and debrisoquine, respectively. Thus, debrisoquine is not a specific CYP2D6 substrate and quinidine is not a specific CYP2D6 inhibitor. These findings have significant implications for the conduct of in vitro drug metabolism inhibition studies and underscore the fallacy of "specific chemical inhibitors" of a supergene family of enzymes that have overlapping substrate specificities. The use of highly specific mAbs in such studies is mandated. It is unclear as yet whether these findings have implications for the relationship between CYP2D6 genotype and in vivo debrisoquine 4-hydroxylase activity.

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confidence: 99%

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Granvil

Krausz²,

Gelboin³

et al. 2002

J Pharmacol Exp Ther

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“…There are few reports in the available literature that concern the role of xenobiotic metabolizing enzyme polymorphism in autoimmune diseases [14, 15, 27]. However, a report about the association of CYP2D6 gene with SLE is still unavailable in Poland.…”

Section: Discussionmentioning

confidence: 99%

“…CYP2D6 polymorphism was also the subject of a study by Kortunay et al . However, the authors failed to show any association between the CYP2D6 genotype and the risk of developing SLE [14]. …”

Section: Discussionmentioning

confidence: 99%

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Genetic polymorphisms of CYP2D6 oxidation in patients with systemic lupus erythematosus

Skrętkowicz¹,

Barańska²,

Kaczorowska³

et al. 2011

aoms

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IntroductionSystemic lupus erythematosus (SLE) is a complex, multifactor autoimmune disease. The studies on aetiopathogenesis of autoimmune diseases focus on the impact the genetically conditioned impairment of xenobiotic metabolism may exert. The knowledge of oxidation polymorphism in the course of SLE may be helpful in choosing more efficient and safer therapy. We determined whether there was an association between susceptibility to SLE and particularly to CYP2D6 genotypes.Material and methodsThe study was carried out in 60 patients with SLE and 129 healthy volunteers and all the subjects were of Polish origin. The samples were analysed for two major defective alles for CYP2D6 – CYP2D6*3 and CYP2D6*4 and one wild -type allele CYP2D6*1-by the polymerase chain reaction fragment length polymorphism (PCR-RFLP) metod with DNA extracted from peripheral blood.ResultsNo statistically significant differences in the incidence of CYP2D6 genotypes between the studied groups were found (p = 0.615). Risk (OR) of SLE development was 1.03 for the carriers of CYP2D6*3 allele and 1.48 for the subjects with CYP2D6*4 allele; but it was not statistically significant.ConclusionsIncreased occurrence of mutant alleles of the CYP2D6 gene in SLE patients and the calculated OR values could suggest the effect of these mutations on increased SLE development.

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“…In general, 71% of CYP2D6 alleles in Caucasian are functional alleles, while nonfunctional alleles represent 26% [31]. CYP2D6*3 (A2637 deletion) and CYP2D6*4 (G1934A point mutation) are the most common nonfunctional alleles [34]. The polymorphisms can result in defective or increased enzyme activity and CYP2D6 genotypes usually exhibit large interethnic differences [35].…”

Section: Introductionmentioning

confidence: 98%

Genetic Polymorphisms of CYP2D6 Oxidation in Patients with Inflammatory Bowel Disease

et al. 2009

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Inflammatory bowel disease (IBD) consists of ulcerative colitis and Crohn's disease, both of which are associated with increased colorectal cancer risk. The relationship between genetically determined polymorphic metabolism of exogenous substances by oxidation catalyzed by CYP2D6 isoenzyme and susceptibility to cancer has aroused great interest. We determined whether there was an association between susceptibility to inflammatory bowel disease and particularly to CYP2D6 genotypes. The study was carried out in 39 patients with IBD. The control group consisted of 129 healthy volunteers. The CYP2D6 genotypes were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method with DNA extracted from peripheral blood. Among 39 patients with inflammatory bowel disease, extensive metabolizer (EM) genotype constituted 97.4%. One patient (2.6%) was poor metabolizer with CYP2D6*4/CYP2D6*4 genotype. Results obtained in the inflammatory bowel disease group did not differ significantly from those of the control group. Although the odds ratio for EM metabolizers was about 3.8-fold greater in the group of patients with inflammatory bowel disease, this association was not statistically significant. This data also showed no overall statistically significant association between alleles and incidence risk of inflammatory bowel disease [odds ratio (OR) of 1.36 for CYP2D6*1 allele, 0.83 for CYP2D6*3 allele, and 0.74 for CYP2D6*4 allele]. The present results suggest that EM genotype may be the risk factor of inflammatory bowel disease. Future studies are needed to confirm our assumptions on larger group of patients.

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CYP2D6 polymorphism in systemic lupus erythematosus patients

Cited by 12 publications

References 15 publications

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

Genetic polymorphisms of CYP2D6 oxidation in patients with systemic lupus erythematosus

Genetic Polymorphisms of CYP2D6 Oxidation in Patients with Inflammatory Bowel Disease

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