Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

Abstract

The thiopurines (6-mercaptopurine [6-MP], 6-thioguanine and azathioprine) are cytotoxic drugs used in the treatment of acute lymphoblastic leukemia (ALL), inflammatory bowel diseases, certain autoimmune diseases and after transplantation. The metabolism of

Pharmacogenetic studies of thiopurine methyltransferase genotype‐phenotype concordance and effect of methotrexate on thiopurine metabolism

“…Results from extended genotyping are included, and where more than one TPMT enzyme activity result was available, the result of the most recent measurement was used in the figure. Reprinted with permission from reference 1 1 …”

“…Reprinted with permission from reference 1. 1 2000 to 2015, the TPMT enzyme activity ranged from 0 to 40.8 U/mL packed red blood cells (pRBC). 21 Of all individuals, 88% showed TPMT enzyme activity within the normal range (≥9.0 U/mL pRBC), 11.6% had intermediate activity, and 0.4% had low activity (<2.5 U/mL pRBC).…”

“…COFACTORS: SAM, S‐adenosyl‐L‐methionine; PRPP, phosphoribosyl pyrophosphate; NAD+, nicotinamide adenine dinucleotide; ATP, adenosine triphosphate, METABOLITES: (T)UA, (thio)uric acid; meMP, methylated mercaptopurine; (T)IMP, (thio)inosine monophosphate; meTIMP, methylated TIMP; (T)XMP, (thio)xanthine monophosphate; (T)GMP, (thio)guanosine monophosphate; TGN (thioguanine nucleotides) includes TdGDP, TdGTP, TGDP and TGTP, thio‐(deoxy)‐guanosine‐mono/di/triphosphate; endogenous nucleotides dGDP, dGTP, GDP and GTP. Reprinted with permission from reference 1 1 …”

“…This MiniReview is based on Zimdahl Kahlin's doctoral thesis. 1 Using a large cohort of clinical samples from nearly 16 000 individuals with requested TPMT status before or during thiopurine treatment, the objectives were to investigate concordance between TPMT genotyping and phenotyping and, in samples where TPMT genotype and phenotype was not in concordance, to describe and characterize previously uncharacterized TPMT alleles found by extended sequencing. In addition, the effect of MTX on the TPMT enzyme and thiopurine metabolism was investigated.…”

“… Parts of the present MiniReview have been published previously in the PhD thesis of Dr Anna Zimdahl Kahlin 1 …”