Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.67 (thiopurine methyltransferase)
551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An investigation has been conducted on the foreign compound-metabolizing activity of human liver collected fresh from surgery or at autopsy from cadavers 3 to 18 hr old, and the effects of low temperature storage on the foreign compound-metabolizing activity of fresh human liver. The enzyme activities studied were microsomal cytochrome P-450 content, biphenyl 4-hydroxylation, benzo-(a)pyrene metabolism, halothane reduction, and 4-hydroxybiphenyl UDP-glucuronosyl transferase, as well as cytosolic thiopurine methyltransferase, thermostable (TS) phenolsulfotransferase, thermolabile (TL) phenolsulfotransferase, and 5-fluorouracil dehydrogenase. Cadaver liver was a poor source of material for metabolism studies with the majority of the enzymes investigated. There was an 84% decrease in the yield of microsomal protein, a 64% decrease in cytochrome P-450 content per mg of microsomal protein, and a 36% decrease in the biphenyl 4-hydroxylase specific activity in human cadaver liver that was a few hours old. UDP-glucuronosyl transferase showed a 70% decrease, TS phenolsulfotransferase a 84% decrease, TL phenolsulfotransferase a 97% decrease, and thiopurine methyltransferase no significant change in specific activity. The loss of activity for many of these enzymes could be simulated by keeping fresh human liver at the temperature of the body after death. Surgical waste provided a good source of fresh, histologically normal, human liver for metabolism studies. Microsomal cytochrome P-450 content showed a significant increase with the age of the liver donor. Metabolism of benzo(a)pyrene to 3-hydroxybenzo(a)pyrene and benzo(a)pyrene-7,8- and -9,10-diols showed up to 136% higher rates in fresh liver microsomes from female donors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Foreign compound metabolism studies with human liver obtained as surgical waste. Relation to donor characteristics and effects of tissue storage. 290 27

Twenty-seven substituted benzoic acids have been studied as inhibitors of partially purified human renal thiopurine methyltransferase (TPMT). Quantitative structure-activity relationship (QSAR) analysis resulted in the following equation: pI50 = 1.25( +/- 0.53)pi'3 + 0.73( +/- 0.38)MR3,4 + 2.92( +/- 0.39). In this equation pI50 is the -log of the concentration of compound that inhibits the enzyme activity by 50% (IC50);pi'3 is the relative hydrophobicity of the more hydrophobic of the two meta substituents; and MR3,4 is the molar refractivity of the more hydrophobic of the two meta substituents and of the para substituent on the phenyl ring. In addition, 14 substituted thiophenols were tested as substrates for the enzyme. All 14 thiophenols tested were excellent substrates with Km constants (0.8-7.8 microM) that were at least 2 orders of magnitude lower than those of any known thiopurine substrate for TPMT. However, there was no discernible relationship between the activities of thiophenol substrates and their physicochemical parameters. These results suggest that benzoic acid inhibitors of and thiophenol substrates for TPMT may interact with different sites on the enzyme.
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PMID:Thiopurine methyltransferase: structure-activity relationships for benzoic acid inhibitors and thiophenol substrates. 395 Sep 15

An investigation was initiated to determine if glutathione is an endogenous substrate for thiopurine methyltransferase. Glutathione, as well as S-methylglutathione, were each capable of inhibiting the enzyme in a concentration-dependent manner, which suggested competitive and product inhibition, respectively. However, radiochromatography revealed that S-methylation of glutathione is not a catalytic activity of this sulfhydryl transmethylase. Subsequent experiments indicated that the inhibitory effects of both glutathione and S-methylglutathione on thiopurine methyltransferase may be due to their acidic natures, changing the reaction mixture pH away from the optimal range for the enzyme.
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PMID:Glutathione: an endogenous substrate for thiopurine methyltransferase? 397 11

Rat liver cytosolic thiopurine methyltransferase and microsomal thiol methyltransferase were each found to be subject to control by the absolute molar ratio of S-adenosylmethionine to S-adenosylhomocysteine using cell-free enzyme preparations. As this ratio was lowered, inhibition of both sulfhydryl xenobiotic transmethylases occurred. On the other hand, when the ratio was decreased in vivo by the administration of D,L-homocysteine thiolactone to animals, this alteration was accompanied by an inhibition of only thiopurine methyltransferase activity. Thiol methyltransferase activity was not significantly affected after drug treatment, which would suggest that there is a compartmentalization of S-adenosylhomocysteine in the intact hepatocyte.
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PMID:Effect of S-adenosylhomocysteine on sulfhydryl xenobiotic transmethylases in rat liver. 399 29

Methyl conjugation is an important pathway in drug metabolism. Activities of three human drug-metabolizing methyltransferase enzymes, catechol-O-methyltransferase (COMT) (EC 2.1.1.6), thiopurine methyltransferase ( TPMT ) (EC 2.1.1.67), and thiol methyltransferase (TMT) (EC 2.1.1.9), are controlled by inheritance. COMT activity in the red blood cell (RBC) is regulated by a single genetic locus with two alleles, COMTL for low activity and COMTH for high activity. Gene frequencies of these two alleles were approximately equal in a white population sample of Northern European origin. The genetically controlled level of COMT activity in the RBC reflects the level of enzyme activity in other tissues and is significantly correlated with individual variations in the methyl conjugation of catechol drugs such as L-dopa and methyldopa. TPMT catalyzes the S-methylation of thiopurines and thiopyrimidines . RBC TPMT activity is also controlled by a single genetic locus with two alleles, TPMTL for low and TPMTH for high activity. The gene frequencies of these two alleles were 0.06 and 0.94, respectively, in a white population sample. RBC TPMT activity reflects the level of enzyme activity in other cells and tissues such as the lymphocyte and kidney. TMT catalyzes the S-methylation of aliphatic sulfhydryl compounds such as the drugs captopril and D-penicillamine. The heritability of the level of RBC membrane TMT activity has been estimated on the basis of family studies to be approximately 0.98. Regulation of these three methyl-conjugating enzymes by inheritance raises the possibility that genetically determined methylator status may be one factor responsible for variations in drug metabolism in humans.
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PMID:Human pharmacogenetics of methyl conjugation. 671 37

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.
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PMID:Toxicity and metabolism in mice of 2,6-dithiopurine, a potential chemopreventive agent. 749 53

Azathioprine-induced myelosuppression is the most important side effect observed in kidney transplantation. We report a case of severe neutropenia after kidney transplantation due to a thiopurine methyltransferase deficiency. This cause of azathioprine-induced myelotoxicity is rare, but its infectious consequences may be severe. Thiopurine methyltransferase deficiency must therefore be suspected when early and severe leukopenia occurs during azathioprine therapy. Erythrocyte thiopurine methyltransferase activity measurement confirms the diagnosis. Azathioprine and 6-mercaptopurine must afterwards be definitively avoided.
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PMID:[Homozygote deficiency of thiopurine methyltransferase. A contraindication to the use of azathioprine in kidney transplantation]. 750 7

We have examined red blood cell (RBC) thiopurine methyltransferase (TPMT) activity in a healthy population sample of Norwegian children, age 1-10 years. Boys had mean RBC TPMT activity of 11.1 +/- 2.0 U (n = 87) vs. 10.6 +/- 2.2 U (n = 71) in girls, the difference was not significant (P = 0.3). Age was negatively correlated to RBC TPMT activity (rs = -0.2, P = 0.01). As boys with acute lymphoblastic leukemia (ALL) tolerate more 6-mercaptopurine (6-MP) than girls and have a higher risk of relapse, we have searched for pharmacokinetic causes of these gender differences. The gender difference in 6-MP tolerance and clinical outcome in children with ALL cannot be explained by the minor and nonsignificant higher RBC TPMT activity in boys compared to girls.
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PMID:Is there a gender difference in red blood cell thiopurine methyltransferase activity in healthy children? 756 6

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.
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PMID:Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. 764 Jan 56

Azathioprine is an immunosuppressor used with ciclosporin and corticosteroids after organ transplantation. Azathioprine is rapidly transformed into 6-mercaptopurine which in turn is metabolized by three competitive pathways: a) intracellular hypoxanthine guanine phosphoribosyl transferase leads to 6-thioguanine nucleotides which can damage chromosome DNA; b) thiopurine methyltransferase produces inactive methylated derivatives; c) xanthine oxidase produces thiouric acid. Due to inter-individual variations in the later two pathways, azathioprine dose must be adapted to each patient. A 48-year-old female patient underwent renal transplantation in 1994 and was given immunosuppressive therapy combining thymoglobulins, azathioprine and ciclosporin. Severe leukopenia (< 3000/mm3) occurred on day 5 requiring withdrawal of azathioprine. Known hypouricaemia (< 50 mumol/l) suggested xanthine oxidase deficiency. Laboratory results confirmed xanthine oxidase deficiency and also revealed reduced thiopurine methyltransferase activity (14.9 pmol/h/mg Hb). Azathioprine toxicity was confirmed by regression of the leukopenia after withdrawal and recurrence at rechallenge. Xanthine oxidase deficiency occurs in 2% of the general population. Reduced thiopurine methyltransferase activity affects 11% of the population. The combined presence of these two genetic anomalies led to early and sudden intolerance to azathioprine and emphasize the need to develop new immunosuppressor agents degraded by other metabolic pathways.
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PMID:[Hematotoxicity caused by azathioprine genetically determined and aggravated by xanthine oxidase deficiency in a patient following renal transplantation]. 766 22


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