PDF herunterladen
Exp Clin Endocrinol Diabetes 2014; 122(01): 60-63
DOI: 10.1055/s-0033-1361097
Short Communication
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

CYP2C9*2 Allele Increases Risk for Hypoglycemia in POR*1/*1 Type 2 Diabetic Patients Treated with Sulfonylureas

G. Ragia
1   Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
,
A. Tavridou
1   Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
2   Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
,
L. Elens
3   Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
4   Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, The Netherlands
,
R. H. N. Van Schaik
4   Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, The Netherlands
,
V. G. Manolopoulos
1   Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
2   Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 07. September 2013
first decision 24. Oktober 2013

accepted 06. November 2013

Publikationsdatum:
24. Januar 2014 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

It is previously shown that carriers of the defective allele CYP2C9*3 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C9*2 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR*28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR*28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C9*2 allele with hypoglycemia risk in non-carriers of POR*28 allele. The study group consisted of 176 patients with diagnosed type 2 diabetes mellitus (T2DM) treated with sulfonylureas, of whom 92 patients had experienced at least one drug-associated hypoglycemic event (cases), while 84 had never experienced a hypoglycemic event (controls). POR*28 allele was detected by use of real-time TaqMan PCR. POR*28 allele was not associated with sulfonyl­urea-induced hypoglycemia. In POR*1/*1 patients, CYP2C9*1/*2 genotype was more common in cases than in controls (32.7 vs. 14.3%, p=0.041). In a model adjusted for age, BMI, duration of T2DM and renal function, and POR*1/*1 entered as a selection variable, CYP2C9*2 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR*28 allele is masking the association of CYP2C9*2 allele with sulfonyl­urea-induced hypoglycemia. Therefore, POR*28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly­morphisms may explain individual variability in the effect of sulfonylureas.

Keywords

sulfonylurea - hypoglycemia - pharmacogenetics - POR*28 - CYP2C9*2
 

  • References

  • 1 Chao J, Nau DP, Aikens JE. Patient-reported perceptions of side effects of antihyperglycemic medication and adherence to medication regimens in persons with diabetes mellitus. Clinical Therapeutics 2007; 29: 177-180
    CrossrefPubMedGoogle Scholar
  • 2 Manolopoulos VG. Pharmacogenomics and adverse drug reactions in diagnostic and clinical practice. Clin Chem Lab Med 2007; 45: 801-814
    PubMedGoogle Scholar
  • 3 Kirchheiner J, Roots I, Goldammer M et al. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2005; 44: 1209-1225
    CrossrefPubMedGoogle Scholar
  • 4 Manolopoulos VG, Ragia G, Tavridou A. Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective. Pharmacogenomics 2011; 12: 1161-1191
    CrossrefPubMedGoogle Scholar
  • 5 Holstein A, Plaschke A, Ptak M et al. Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents. Br J Clin Pharmacol 2005; 60: 103-106
    CrossrefPubMedGoogle Scholar
  • 6 Ragia G, Petridis I, Tavridou A et al. Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics 2009; 10: 1781-1787
    CrossrefPubMedGoogle Scholar
  • 7 Gokalp O, Gunes A, Cam H et al. Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting. Eur J Clin Pharmacol 2011; 67: 1223-1229
    CrossrefPubMedGoogle Scholar
  • 8 Rettie AE, Wienkers LC, Gonzalez FJ et al. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4: 39-42
    CrossrefPubMedGoogle Scholar
  • 9 Johnson JA, Klein TE, Relling MV. Clinical implementation of pharmacogenetics: more than one gene at a time. Clin Pharmacol Ther 2013; 93: 384-385
    CrossrefPubMedGoogle Scholar
  • 10 Subramanian M, Agrawal V, Sandee D et al. Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3. Pharmacogenet Genomics 2012; 22: 590-597
    CrossrefPubMedGoogle Scholar
  • 11 Fluck CE, Nicolo C, Pandey AV. Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase. Fundam Clin Pharmacol 2007; 21: 399-410
    CrossrefPubMedGoogle Scholar
  • 12 Riddick DS, Ding X, Wolf CR et al. NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology. Drug Metab Dispos 2013; 41: 12-23
    CrossrefPubMedGoogle Scholar
  • 13 Gomes AM, Winter S, Klein K et al. Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics 2009; 10: 579-599
    CrossrefPubMedGoogle Scholar
  • 14 Huang N, Agrawal V, Giacomini KM et al. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci USA 2008; 105: 1733-1738
    CrossrefPubMedGoogle Scholar
  • 15 Ragia G, Tavridou A, Petridis I et al. Association of KCNJ11 E23K gene polymorphism with hypoglycemia in sulfonylurea-treated type 2 diabetic patients. Diabetes Res Clin Pract 2012; 98: 119-124
    CrossrefPubMedGoogle Scholar
  • 16 Oneda B, Crettol S, Jaquenoud Sirot E et al. The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test. Pharmacogenet Genomics 2009; 19: 877-883
    CrossrefPubMedGoogle Scholar
  • 17 Yang G, Fu Z, Chen X et al. Effects of the CYP oxidoreductase Ala503Val polymorphism on CYP3A activity in vivo: a randomized, open-label, crossover study in healthy Chinese men. Clin Ther 2011; 33: 2060-2070
    CrossrefPubMedGoogle Scholar