MTHFR and TYMS genotypes influence TPMT activity and its differential modulation in males and females

Karas-Kuzelicki, Natasa; Milek, Miha; Mlinarič-Raščan, Irena

doi:10.1016/j.clinbiochem.2009.09.003

Cited by 21 publications

(9 citation statements)

References 29 publications

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“…Females were at a higher risk of leukopenia than males ( P = 0.0006; OR = 2.32; 95% CI, 1.27–4.24). Similar findings have been previously described in the researches, which could possibly be explained by recent data showing a significantly lower TPMT activity in females as compared with males . Meanwhile, drug clearance in general is lower in females and tends to decrease with age in both genders, which is the most likely explanation for these findings.…”

Section: Discussionsupporting

confidence: 90%

NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease

Zhu

Wang

Chao

et al. 2016

Aliment Pharmacol Ther

106

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Section: Discussionsupporting

confidence: 90%

NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease

Zhu

Wang

Chao

et al. 2016

Aliment Pharmacol Ther

106

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“…A gender difference has been reported in the distribution of red cell TPMT activities in some but not all studies , with wild‐type TPMT infants less than 2 years having a higher activity in boys than girls . Hepatic activity (measured in patient surgical biopsy tissue) was significantly higher in men than women; but this difference was not reflected in measurements of red cell TPMT activity .…”

Section: Measurement Of Tpmt Statusmentioning

confidence: 97%

Implementation of TPMT testing

Lennard

2014

Brit J Clinical Pharma

114

115

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The activity of the enzyme thiopurine methyltransferase (TPMT) is regulated by a common genetic polymorphism. One in 300 individuals lack enzyme activity and 11% are heterozygous for a variant low activity allele and have an intermediate activity. The thiopurine drugs azathioprine, mercaptopurine and thioguanine are substrates for TPMT; these drugs exhibit well documented myelosuppressive effects on haematopoietic cells and have a track record of idiosyncratic drug reactions. The development of severe bone marrow toxicity, in patients taking standard doses of thiopurine drugs, is associated with TPMT deficiency whilst the TPMT heterozygote is at an increased risk of developing myelosuppression. Factors influencing TPMT enzyme activity, as measured in the surrogate red blood cell, are discussed in this review to enable an appreciation of why concordance between TPMT genotype and phenotype is not 100%. This is particularly important for lower/intermediate TPMT activities to avoid misclassification of TPMT status. TPMT testing is now widely available in routine service laboratories. The British National Formulary suggests TPMT testing before starting thiopurine drugs. Dermatologists were quick to adopt routine TPMT testing whilst gastroenterologists do not specifically recommend TPMT screening. TPMT testing is mandatory prior to the use of mercaptopurine in childhood leukaemia. Thiopurine drug dose and other treatment related influences on cell counts explain some of the differing recommendations between clinical specialities. TPMT testing is cost-effective and the major role is in the identification of the TPMT deficient individual prior to the start of thiopurine drugs.

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“…In particular, 5,10‐methylene tetrahydrofolate reductase (MTHFR) presents different genetic polymorphisms, two of which occur in 20% of the general population and are associated with decreased enzyme activity 216 . A genetic study on 86 healthy individuals showed an influence of these MTHFR genetic polymorphisms on TPMT activity 217 . However, Breen et al.…”

Section: Newly Identified Pharmacogenetic Factors Contributing To Varmentioning

confidence: 99%

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

Chouchana

Narjoz

Beaune

et al. 2011

Aliment Pharmacol Ther

147

142

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Aliment Pharmacol Ther 2012; 35: 15–36 Summary Background Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter‐individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. Aim To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic‐based therapeutic recommendations. Methods We conducted a query on PubMed database using ‘inflammatory bowel disease’, ‘thiopurine’, ‘azathioprine’, ‘6‐mercaptopurine’, ‘TPMT’, ‘pharmacogenetics’, ‘TDM’, and selected relevant articles, especially clinical studies. Results Thiopurine metabolism – key enzyme: thiopurine S‐methyltransferase (TPMT) – modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6‐TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S‐transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP‐binding cassette sub‐family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. Conclusions Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.

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MTHFR and TYMS genotypes influence TPMT activity and its differential modulation in males and females

Cited by 21 publications

References 29 publications

NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease

NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease

Implementation of TPMT testing

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

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