PMID- 2758725
OWN - NLM
STAT- MEDLINE
DCOM- 19890921
LR  - 20190510
IS  - 0009-9236 (Print)
IS  - 0009-9236 (Linking)
VI  - 46
IP  - 2
DP  - 1989 Aug
TI  - Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine 
      methyltransferase genetic polymorphism.
PG  - 149-54
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 Azathioprine was withdrawn in five study patients because of acute 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.
FAU - Lennard, L
AU  - Lennard L
AD  - University Department of Pharmacology and Therapeutics, Royal Hallamshire 
      Hospital, Sheffield, U.K.
FAU - Van Loon, J A
AU  - Van Loon JA
FAU - Weinshilboum, R M
AU  - Weinshilboum RM
LA  - eng
GR  - 28157/PHS HHS/United States
GR  - 55110/PHS HHS/United States
GR  - GM 35720/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adult
MH  - Azathioprine/metabolism/*toxicity
MH  - Bone Marrow/drug effects
MH  - Erythrocytes/analysis
MH  - Female
MH  - Guanine Nucleotides/blood
MH  - Humans
MH  - Male
MH  - Methyltransferases/*blood
MH  - Middle Aged
MH  - *Polymorphism, Genetic
MH  - Thionucleotides/blood
EDAT- 1989/08/01 00:00
MHDA- 1989/08/01 00:01
CRDT- 1989/08/01 00:00
PHST- 1989/08/01 00:00 [pubmed]
PHST- 1989/08/01 00:01 [medline]
PHST- 1989/08/01 00:00 [entrez]
AID - 0009-9236(89)90353-6 [pii]
AID - 10.1038/clpt.1989.119 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 1989 Aug;46(2):149-54. doi: 10.1038/clpt.1989.119.