Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism

L. Lennard, J. A. Van Loon, Richard M Weinshilboum

Research output: Contribution to journalArticle

484 Citations (Scopus)

Abstract

Azathioprine therapy can cause acute myelosuppression. Toxicity is in part caused by the incorporation of azathioprine-derived 6-thioguanine nucleotides (6-TGN) into deoxyribonucleic acid (DNA). The enzyme thiopurine methyltransferase (TPMT) plays an important role in azathioprine catabolism. TPMT activity is controlled by a common genetic polymorphism, and one in 300 subjects has very low enzyme activity. Azathioprine was withdrawn in five study patients because of acute myelosuppression. The duration of azathioprine treatment was 21 to 70 days (median, 28), and the daily oral dose was 1.0 to 2.5 mg/kg. Sixteen control patients who had been taking oral azathioprine (1.1 to 2.0 mg/kg daily for more than 6 months) with no history of myelosuppression were studied. All subjects had normal liver and kidney function. When compared with the control group, the five patients with myelosuppression had very low TPMT activities and abnormally high 6-TGN concentrations. Inherited low TPMT activity appears to be a major risk factor for acute azathioprine-induced myelosuppression.

Original languageEnglish (US)
Pages (from-to)149-154
Number of pages6
JournalClinical Pharmacology and Therapeutics
Volume46
Issue number2
StatePublished - 1989

Fingerprint

thiopurine methyltransferase
Pharmacogenetics
Azathioprine
Genetic Polymorphisms
Enzymes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Pharmacogenetics of acute azathioprine toxicity : Relationship to thiopurine methyltransferase genetic polymorphism. / Lennard, L.; Van Loon, J. A.; Weinshilboum, Richard M.

In: Clinical Pharmacology and Therapeutics, Vol. 46, No. 2, 1989, p. 149-154.

Research output: Contribution to journalArticle

@article{34c4c2c589334d5d93a6ba68a51751bf,
title = "Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism",
abstract = "Azathioprine therapy can cause acute myelosuppression. Toxicity is in part caused by the incorporation of azathioprine-derived 6-thioguanine nucleotides (6-TGN) into deoxyribonucleic acid (DNA). The enzyme thiopurine methyltransferase (TPMT) plays an important role in azathioprine catabolism. TPMT activity is controlled by a common genetic polymorphism, and one in 300 subjects has very low enzyme activity. Azathioprine was withdrawn in five study patients because of acute myelosuppression. The duration of azathioprine treatment was 21 to 70 days (median, 28), and the daily oral dose was 1.0 to 2.5 mg/kg. Sixteen control patients who had been taking oral azathioprine (1.1 to 2.0 mg/kg daily for more than 6 months) with no history of myelosuppression were studied. All subjects had normal liver and kidney function. When compared with the control group, the five patients with myelosuppression had very low TPMT activities and abnormally high 6-TGN concentrations. Inherited low TPMT activity appears to be a major risk factor for acute azathioprine-induced myelosuppression.",
author = "L. Lennard and {Van Loon}, {J. A.} and Weinshilboum, {Richard M}",
year = "1989",
language = "English (US)",
volume = "46",
pages = "149--154",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Pharmacogenetics of acute azathioprine toxicity

T2 - Relationship to thiopurine methyltransferase genetic polymorphism

AU - Lennard, L.

AU - Van Loon, J. A.

AU - Weinshilboum, Richard M

PY - 1989

Y1 - 1989

N2 - Azathioprine therapy can cause acute myelosuppression. Toxicity is in part caused by the incorporation of azathioprine-derived 6-thioguanine nucleotides (6-TGN) into deoxyribonucleic acid (DNA). The enzyme thiopurine methyltransferase (TPMT) plays an important role in azathioprine catabolism. TPMT activity is controlled by a common genetic polymorphism, and one in 300 subjects has very low enzyme activity. Azathioprine was withdrawn in five study patients because of acute myelosuppression. The duration of azathioprine treatment was 21 to 70 days (median, 28), and the daily oral dose was 1.0 to 2.5 mg/kg. Sixteen control patients who had been taking oral azathioprine (1.1 to 2.0 mg/kg daily for more than 6 months) with no history of myelosuppression were studied. All subjects had normal liver and kidney function. When compared with the control group, the five patients with myelosuppression had very low TPMT activities and abnormally high 6-TGN concentrations. Inherited low TPMT activity appears to be a major risk factor for acute azathioprine-induced myelosuppression.

AB - Azathioprine therapy can cause acute myelosuppression. Toxicity is in part caused by the incorporation of azathioprine-derived 6-thioguanine nucleotides (6-TGN) into deoxyribonucleic acid (DNA). The enzyme thiopurine methyltransferase (TPMT) plays an important role in azathioprine catabolism. TPMT activity is controlled by a common genetic polymorphism, and one in 300 subjects has very low enzyme activity. Azathioprine was withdrawn in five study patients because of acute myelosuppression. The duration of azathioprine treatment was 21 to 70 days (median, 28), and the daily oral dose was 1.0 to 2.5 mg/kg. Sixteen control patients who had been taking oral azathioprine (1.1 to 2.0 mg/kg daily for more than 6 months) with no history of myelosuppression were studied. All subjects had normal liver and kidney function. When compared with the control group, the five patients with myelosuppression had very low TPMT activities and abnormally high 6-TGN concentrations. Inherited low TPMT activity appears to be a major risk factor for acute azathioprine-induced myelosuppression.

UR - http://www.scopus.com/inward/record.url?scp=0024451147&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024451147&partnerID=8YFLogxK

M3 - Article

C2 - 2758725

AN - SCOPUS:0024451147

VL - 46

SP - 149

EP - 154

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 2

ER -