Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II)
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F18%3A10377545" target="_blank" >RIV/00216208:11110/18:10377545 - isvavai.cz</a>
Alternative codes found
RIV/00023728:_____/18:N0000088 RIV/00064165:_____/18:10377545
Result on the web
<a href="https://doi.org/10.1016/j.taap.2018.06.015" target="_blank" >https://doi.org/10.1016/j.taap.2018.06.015</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.taap.2018.06.015" target="_blank" >10.1016/j.taap.2018.06.015</a>
Alternative languages
Result language
angličtina
Original language name
Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II)
Original language description
Background: The aim of our study was to identify the genetic background of thiopurine-induced toxicity in a patient with a wild-type thiopurine methyltransferase genotype and activity. A 38-year-old Caucasian woman presented with cutaneous necrotizing vasculitis pancytopenia one month after starting azathioprine therapy. Methods: During a routine biochemical follow-up of the patient, undetectable serum uric acid (<10 μl) was observed. A high performance liquid chromatography analysis of urinary purines revealed increased levels of xanthine (137 mmol/mol creatinine). The suspected diagnosis of hereditary xanthinuria, a rare autosomal recessive disorder of the last two steps of purine metabolism, was confirmed by sequence analysis. Results: An analysis of XDH/XO and AOX1 revealed common polymorphisms, while analysis of the MOCOS gene identified a rare homozygous variant c.362C > T. Dysfunction of this variant was confirmed by significantly decreased xanthine dehydrogenase/oxidase activity in the patient's plasma (<2% of control mean activity). Conclusions: We present a biochemical, enzymatic, and molecular genetic case study suggesting an important association between a hitherto undescribed dysfunction variant in the MOCOS gene and thiopurine-induced toxicity. The identified variant c.362C > T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30226 - Rheumatology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Toxicology and Applied Pharmacology
ISSN
0041-008X
e-ISSN
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Volume of the periodical
353
Issue of the periodical within the volume
August
Country of publishing house
US - UNITED STATES
Number of pages
7
Pages from-to
102-108
UT code for WoS article
000440125400010
EID of the result in the Scopus database
2-s2.0-85048877097