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Biomedical subjects

C L Szumlanski

Publications and source records attributed to C L Szumlanski.

18 recordsLinked to original sources
PubMed2001

Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.

AIM: We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine. METHODS: Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts < 3.0 x 10(9)/l and < or = 3.5 x 10(9)/l. Whole blood 6-thioguanine nucleotide concentrations were determined. RESULTS: Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts < 3.0 and < or = 3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group. CONCLUSIONS: In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leucopenia.

Adult↗
PubMed2000

Histamine N-methyltransferase functional polymorphism: lack of association with schizophrenia.

Histamine is a central nervous system (CNS) neurotransmitter that has been implicated in the pathophysiology of schizophrenia. Histamine N-methyltransferase (HNMT) terminates the neurotransmitter actions of histamine in the mammalian CNS, and levels of HNMT activity in human tissues are controlled, in part, by inheritance. A common C314T polymorphism in the HNMT gene causes a Thr105Ile change in encoded amino acid. The T314 allele results in decreased levels of both HNMT enzyme activity and immunoreactive protein. There is also a polymorphic CA repeat in intron 5 of the HNMT gene. The frequencies of alleles for the functional C314T polymorphism and the polymorphic CA repeat were compared between 171 schizophrenia cases and 171 ethnically matched controls to test for possible disease association. No significant difference was found between the two groups in the frequency of the T314 allele in patients with schizophrenia and controls (0.068 vs. 0.078, respectively). Allele frequencies for the polymorphic HNMT CA repeat also failed to show significant differences between cases and matched controls.

Alleles↗
PubMed2000

Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis.

BACKGROUND: Thiopurine methyltransferase (TPMT) is a genetically polymorphic enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. Recently, a variable number tandem repeat (VNTR) within the TPMT promoter has been reported to "modulate" levels of this enzyme activity. METHODS: We set out to perform genotype-phenotype correlation analysis for the polymorphic TPMT tandem repeat in 1211 clinical laboratory samples in which red blood cell (RBC) TPMT activity had been measured and to compare those results with data for 279 control DNA samples. RESULTS: TPMT VNTR length varied from three to nine repeats ( *V3 to *V9), but the most common alleles were *V4 and *V5, with frequencies in the control samples of 0.54 and 0.36, respectively. The clinical laboratory samples were then stratified into those with "low," "intermediate," or "high" levels of RBC TPMT activity; that is, samples presumed to be homozygous for open reading frame (ORF)-based variant alleles, heterozygous for those alleles, or homozygous for the "wild-type" ORF sequence, respectively. TPMT VNTR genotype *V4/*V5 was associated with significantly higher RBC TPMT activity than were *V4/*V4 or *V5/*V5. Lowest activity levels were associated with genotypes that included an allele with more than 5 repeat elements. However, all of these effects were quantitatively small. Finally, there was linkage disequilibrium between VNTR allele *V5 and TPMT*3A, the most common ORF-based polymorphism associated with very low TPMT activity in white persons. CONCLUSIONS: These observations suggest that, in addition to the striking effects of ORF-based single nucleotide polymorphisms on TPMT activity, the VNTR within the 5'-flanking region of the TPMT gene also may modulate levels of RBC TPMT activity.

Adolescent↗
PubMed1999

Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase.

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.

Animals↗
PubMed1998

Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity.

Thiopurine methyltransferase (TPMT) catalyzes S-methylation of thiopurine drugs such as 6-mercaptopurine. Large variations in levels of TPMT activity in human tissue can result from a common genetic polymorphism with a series of alleles for low activity. This polymorphism is an important factor responsible for large individual variations in thiopurine toxicity and therapeutic efficacy. We now report a new variant allele, TPMT*4, that contains a G--> A transition that disrupts the intron/exon acceptor splice junction at the final 3' nucleotide of intron 9, the terminal intron of the TPMT gene. This new allele cosegregated within an extended kindred with reduced TPMT activity. We attempted to determine the mechanism(s) by which the presence of TPMT*4 might result in low enzyme activity. Although very few mature transcripts derived from allele TPMT*4 were detected, the mutation did lead to generation of at least two aberrant mRNA species. The first resulted from use of a novel splice site located one nucleotide 3' downstream from the original splice junction. That mRNA species contained a single nucleotide deletion and a frameshift within exon 10, the terminal exon of the gene. The second novel mRNA species resulted from activation of a cryptic splice site located within intron 9, leading to inclusion of 330 nucleotides of intron sequence. That sequence contained a premature translation termination codon. TPMT*4 is the first reported allele for low TPMT activity as a result of a mutation within an intron. These observations also provide insight into mechanisms of mRNA processing after disruption of a terminal exon splice junction.

Adenine↗
PubMed1998

Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity.

Histamine N-methyltransferase (HNMT) catalyzes a major pathway in histamine metabolism. Levels of HNMT activity in humans are regulated by inheritance. We set out to study the molecular basis for this genetic regulation. Northern blot analysis showed that HNMT is highly expressed in the kidney, so we determined levels of enzyme activity and thermal stability in 127 human renal biopsy samples. DNA was isolated from 12 kidney samples with widely different HNMT phenotypes, and exons of the HNMT gene were amplified with the polymerase chain reaction. In these 12 samples, we observed a C314T transition that resulted in a Thr105Ile change in encoded amino acid, as well as an A939G transition within the 3'-untranslated region. All remaining renal biopsy samples then were genotyped for these two variant sequences. Frequencies of the alleles encoding Thr105 and Ile105 in the 114 samples studied were 0.90 and 0.10, respectively, whereas frequencies for the nucleotide A939 and G alleles were 0.79 and 0.21, respectively. Kidney samples with the allele encoding Ile105 had significantly lower levels of HNMT activity and thermal stability than did those with the allele that encoded Thr105. These observations were confirmed by transient expression in COS-1 cells of constructs that contained all four alleles for these two polymorphisms. COS-1 cells transfected with the Ile105 allele had significantly lower HNMT activity and immunoreactive HNMT protein than did those transfected with the Thr105 allele. These observations will make it possible to test the hypothesis that genetic polymorphisms for HNMT may play a role in the pathophysiology of human disease.

Adult↗
PubMed1997

Human erythrocyte protein L-isoaspartyl methyltransferase: heritability of basal activity and genetic polymorphism for thermal stability.

Protein L-isoaspartyl methyltransferase (PIMT) is believed to play an important role in the disposition of age-damaged proteins by catalyzing the repair of abnormal isoaspartyl linkages resulting from the spontaneous deamidation of asparaginyl residues or isomerization of aspartyl residues. As a step toward testing the hypothesis that human disease- or age-related pathology might be associated with a deficiency in PIMT, we investigated basal activity and thermal stability of PIMT in erythrocyte lysates from 299 U.S. family members. Thermal stability was measured because it is a sensitive measure of variation in amino acid sequence. Basal activity was normally distributed with a mean+/-SD of 558+/-43 units/ml erythrocytes. Statistical analysis of the data revealed that basal PIMT activity exhibited a high degree of heritability. Enzyme thermal stability showed a skewed bimodal frequency distribution, and segregation analysis of family member pedigrees was consistent with Mendelian inheritance of two major alleles. No DNA was available from the family samples, so we tested two additional population samples for a known Ile/Val polymorphism at codon 119 and for PIMT activity and thermal stability, using blood donated by 25 Norwegians and by 20 Koreans. Single-stranded conformational polymorphism analysis using polymerase chain reaction revealed a 100% correlation between thermal stability grouping and this polymorphism. The high thermal stability samples were all homozygous Ile, the low thermal stability samples were all homozygous Val, and the intermediate thermal stability samples were all heterozygous. Furthermore, this polymorphism was responsible, in part, for the variation observed in basal erythrocyte PIMT activity. These results will help provide a foundation for future studies aimed at correlating levels of PIMT activity, or other properties of this enzyme, with human disease.

Aging↗
PubMed1997

Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction.

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 1.2 U per milliliter red blood cells (low normal range) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

Adolescent↗
PubMed1996

Mouse liver nicotinamide N-methyltransferase pharmacogenetics: biochemical properties and variation in activity among inbred strains.

Nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and other pyridines. Human liver NNMT activity shows large individual variations and a bimodal frequency distribution, raising the possibility that this activity, like those of many other methyltransferase enzymes, might be regulated by a genetic polymorphism. In an attempt to develop an experimental animal model for pharmacogenetic studies of NNMT, we determined optimal conditions for the measurement of hepatic NNMT activity in C57BL/6J mice. Mouse liver NNMT was a cytoplasmic enzyme with a pH optimum of 7.4 and apparent Km values for nicotinamide and S-adenosyl-L-methionine, cosubstrates for the reaction, of 370 and 6.5 microM, respectively. These properties were very similar to those of human liver NNMT, as was the relative sensitivity of the mouse liver enzyme to a series of methyltransferase inhibitors. Hepatic NNMT activity was then measured in tissue from male mice of 10 inbred strains. Average levels of NNMT activity in these strains varied by up to 14-fold and ranged from 1.13 +/- 0.18 U per mg protein (mean +/- SEM, n = 6) for C3H/HeJ mice to 16.0 +/- 1.16 U per mg protein in C57BR/cdJ animals. Average hepatic NNMT activities in female mice of six strains in which both sexes were studied varied from five-fold higher than those in males for "low activity' strains, to not significantly different for "high activity' strains. A series of properties of NNMT was then compared in hepatic cytosol from male mice of three different strains - one with "low' (C3H/HeJ), one with "intermediate' (DBA/2J), and one with "high' (C57BL/6J) hepatic NNMT activity. There were no striking differences among these three strains in hepatic NNMT pH optimum, substrate kinetics, IC50 values for inhibitors, thermal stability or behavior during ion exchange chromatography. The existence of large strain and gender-dependent variation in hepatic NNMT activity will make it possible to use inbred mice for studies of the role of inheritance and gender in the regulation of NNMT activity in this species, as well as for studies of the potential pharmacological and toxicological consequences of variation in this important drug-metabolizing enzyme activity.

Amodiaquine↗
PubMed1996

Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders.

Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.

Catechol O-Methyltransferase↗
PubMed1995

Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine.

Thiopurine drugs are used in the treatment of inflammatory bowel disease--as are sulphasalazine and its metabolite 5-aminosalicylic acid (ASA). S-Methylation catalyzed by thiopurine methyltransferase (TPMT) is a major pathway in the metabolism of thiopurines. The hypothesis was tested that TPMT might be inhibited by sulphasalazine or isomers of ASA. Sulphasalazine as well as 3-, 4- and 5-ASA inhibited recombinant human TPMT, with IC50 values of 78, 99, 2600 and 1240 microM, respectively. Kinetic studies demonstrated that the inhibition of TPMT by sulphasalazine and ASA isomers was non-competitive with regard to the thiopurine substrate, 6-MP, and was uncompetitive with regard to the methyl donor for the reaction, S-adenosyl-L-methionine. Our observations raise the possibility of a clinically significant drug-drug interaction in patients treated simultaneously with sulphasalazine and thiopurine drugs.

Aminosalicylic Acids↗
PubMed1995

Toxicity and metabolism in mice of 2,6-dithiopurine, a potential chemopreventive agent.

2,6-Dithiopurine (DTP) has been proposed as a possible chemopreventive agent because of its facile reaction with the electrophilic ultimate carcinogen, benzo[a]pyrene diol epoxide, and other reactive electrophiles. Previous studies in mouse skin indicated almost complete inhibition of benzo[a]pyrene diol epoxide-induced tumorigenesis by DTP, suggesting the possible utility of this compound as a chemopreventive agent. However, little is known of the metabolism of DTP or of its possible long-term toxicity. Mice were fed diets containing up to 4% DTP in AIN-76A for a period of 7 weeks, and possible toxicity was monitored by weight gain and histopathological examination of all major tissues. No toxicity was observed at any dose of DTP. DTP was found to be a good substrate in vitro for two enzymes known to metabolize 6-mercapto-purine: xanthine oxidase and thiopurine methyltransferase. The in vitro metabolites were 2,6-dithiouric acid and an apparent monomethylated derivative, respectively. In vivo, the major urinary metabolite was 2,6-dithiouric acid, which attained levels as high as 34 mM in the urine of mice receiving the 4% DTP diet. DTP was also excreted unchanged in the feces and urine. DTP, 2,6-dithiouric acid, and an unidentified, relatively nonpolar metabolite were also detected in the serum of experimental animals. Although large interindividual variation in the serum DTP concentration was found, there was a dose-dependent increase in serum DTP as the dietary level of DTP was increased. These results suggest that neither toxicity nor metabolism will severely limit the utility of DTP as a chemopreventive agent.

Algorithms↗
PubMed1994

Purine substrates for human thiopurine methyltransferase.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). A genetic polymorphism regulating TPMT activity in human tissue is an important factor responsible for individual differences in the toxicity and therapeutic efficacy of these drugs. Because of the clinical importance of this polymorphism, we studied 18 purine derivatives, including ribonucleosides and ribonucleotides, as potential substrates for purified human kidney TPMT. Sixteen of the compounds studied were substrates for the enzyme, with Km values that varied from 29.1 to 1270 microM and with Vmax values that varied from 75 to 2340 U/mg protein. The thiopurines tested had Km values that were uniformly lower than were those of the corresponding ribonucleosides or ribonucleotides. 6-Selenopurine derivatives had the lowest Km values of the compounds studied. Finally, oxidized purines with an OH in the 8-position were methylated by the enzyme, but 2-OH compounds were potent inhibitors of TPMT.

Humans↗
PubMed1994

Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization.

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide and other pyridines. Human liver NNMT activity has a bimodal frequency distribution, an observation which raises the possibility that this enzyme activity might be regulated by a genetic polymorphism, a polymorphism that could have functional implications for individual differences in drug and xenobiotic toxicity. As a first step toward testing that hypothesis, we set out to clone and express a cDNA for human liver NNMT. Human liver NNMT was partially purified, photoaffinity-labeled, subjected to limited proteolysis, and partial amino acid sequence information was obtained. The polymerase chain reaction was then used to amplify a 550-nucleotide sequence with human liver cDNA as template and primers designed on the basis of the NNMT amino acid sequence. The 5'- and 3'-ends of a human liver NNMT cDNA were obtained by use of the rapid amplification of cDNA ends. The combined use of these approaches resulted in the isolation of a human liver NNMT cDNA that was 969 nucleotides in length, with a 792-nucleotide open reading frame that encoded a 264-amino acid protein with a calculated molecular mass of 29.6 kDa. The human liver NNMT cDNA was transcribed in vitro and translated with a reticulocyte lysate system to yield a protein with a molecular mass of approximately 29 kDa that comigrated during SDS-polyacrylamide gel electrophoresis with photoaffinity-labeled human liver NNMT. The NNMT cDNA was also subcloned into the eukaryotic expression vector p91023(B). COS-1 cells transfected with this construct expressed a high level of NNMT enzymatic activity, and the biochemical properties of this activity were similar to those of human liver NNMT. Human liver NNMT and transfected COS-1 cell NNMT had apparent Km values for the two cosubstrates for the reaction, nicotinamide and S-adenosyl-L-methionine, of 0.43 and 0.38 mM and of 1.8 and 2.2 microM, respectively. IC50 values for the inhibition of NNMT by N1-methylnicotinamide were 60 and 30 microns for human liver and COS-1 cell-expressed NNMT, respectively. Cloning of a cDNA for human liver NNMT will help make it possible to test the hypothesis that inheritance may play a role in the regulation of individual differences in human liver NNMT activity.

Amino Acid Sequence↗
PubMed1992

Human kidney thiopurine methyltransferase. Photoaffinity labeling with S-adenosyl-L-methionine.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of heterocyclic and aromatic sulfhydryl compounds such as the thiopurine drug 6-mercaptopurine (6-MP). TPMT activity in human tissue is regulated by a common genetic polymorphism, and "pharmacogenetic" variation in TPMT activity is an important factor in individual differences in thiopurine drug metabolism, toxicity and therapeutic efficacy. Human renal tissue contains two isozymes of TPMT, Peak I and Peak II, that can be separated by ion exchange chromatography. Our experiments were performed to determine whether S-adenosyl-L-methionine (Ado-Met), the methyl donor for the TPMT reaction, could be used as a photoaffinity ligand for these isozymes as one step in the study of the molecular basis for the TPMT genetic polymorphism. When [3H-methyl]Ado-Met and partially purified preparations of either isozyme of human kidney TPMT were exposed to ultraviolet light at 254 nm, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a 35 kDa protein was the predominant species that was radioactively labeled. The same 35 kDa protein was photoaffinity labeled with [14C-carboxyl]Ado-Met, demonstrating that labeling involved covalent binding of Ado-Met rather than methylation of the protein. TPMT enzymatic activity co-eluted with the 35 kDa protein during sequential DEAE ion exchange, gel filtration and hydroxylapatite chromatography. Inhibitors of TPMT enzymatic activity including S-adenosyl-L-homocysteine, sinefungin, 6-methylmercaptopurine and 3,4-dimethoxy-5-hydroxybenzoic acid inhibited photoaffinity labeling of the 35 kDa protein in preparations of both TPMT Peak I and Peak II isozymes in a concentration-dependent fashion, as did 6-MP, the methyl acceptor substrate for the TPMT reaction. All of these results were compatible with the conclusion that the 35 kDa protein was TPMT. Photoaffinity labeling of TPMT with [3H]Ado-Met should make it possible to purify the enzyme to homogeneity and to study amino acid sequences at or near its active site.

Adenosine↗
PubMed1992

Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes.

Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP). TPMT activity in the human red blood cell (RBC) is controlled by a common genetic polymorphism. Gene frequencies for this polymorphism are such that approximately one in 300 subjects is homozygous for the allele for low activity and lacks RBC TPMT activity, 11% of subjects are heterozygous and have intermediate levels of enzyme activity and 89% are homozygous for the allele for high activity. Our experiments were performed to determine whether the properties of TPMT in an important human drug metabolizing organ, the liver, were similar to those of RBC TPMT and to test the hypothesis that the genetic polymorphism which controls TPMT activity in the human RBC might also regulate the level of this enzyme activity in hepatic tissue. Human liver TPMT is a cytoplasmic enzyme and the Km values for 6-MP and S-adenosyl-L-methionine, cosubstrates for the reaction, were 580 microM and 2.7 microM, respectively. These properties, as well as the sensitivity of human liver TPMT to a panel of methyltransferase inhibitors, were similar to those of RBC TPMT. The enzyme activity was then measured in 119 surgical biopsy samples of hepatic tissue. Average hepatic TPMT activity was 13.6% higher in samples from male than in those from female patients. Frequency distribution histograms demonstrated the presence of a subgroup with intermediate enzyme activity that included 8.4% of samples. In addition, when TPMT activity was measured in both RBCs and hepatic tissue for 35 patients, those with inherited intermediate levels of RBC TPMT activity also had intermediate hepatic enzyme activity. Finally, ion exchange chromatography demonstrated the presence of two isozymes of TPMT in human hepatic tissue, but the isozymes did not appear to explain the molecular mechanism responsible for the genetic polymorphism. These results were compatible with the conclusion that the genetic polymorphism which controls TPMT activity in the RBC also controls levels of this important enzyme activity in a major human drug metabolizing organ, the liver.

Adult↗
PubMedDate not supplied

Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency.

6-thioguanine (6TG) is undergoing investigation for use in the maintenance phase of acute lymphoblastic leukemia (ALL). Just as with 6-mercaptopurine (6MP), it is be expected that 6TG would cause pancytopenia in individuals with inherited thiopurine methyltransferase (TPMT) deficiency. We report the first case of severe and prolonged pancytopenia caused by 6-thioguanine in an 8-year-old boy with ALL and inherited TPMT deficiency. Neutropenia lasted 67 days, whereas anemia and thrombocytopenia did not recover for 96 days. To obviate this life-threatening complication, clinicians should consider assaying TPMT activity before initiating therapy with 6MP and, particularly, 6TG in children with ALL.

Antimetabolites, Antineoplastic↗