Thiopurines

In addition to the rather scattered data reported in the previous survey (76AHCSl,p. 510), a few new studies appeared on purine-6- and -2-thiones. Tire MO calculations of solvent effects (AMl-SMl and AM1-SM2) on the tautomerism of 6-thiopurine indicated that l//,9//-tautomer 7a is greatly stabilized in aqueous solution [94THE(309)137].Tlie same results were obtained experimentally from UV and and NMR studies (75JA3215, 75JA4627,75JA4636). 

MO studies (AMI and AMI-SMI) on the tautomerism and protonation of 2-thiopurine have been reported [95THE(334)223]. Heats of formation and relative energies have been calculated for the nine tautomeric forms in the gas phase. Tire proton affinities were determined for the most stable tautomers 8a-8d. Tire pyrimidine ring in the thiones 8a and 8b has shown a greater proton affinity in comparison with the imidazole ring, or with the other tautomers. In solution, the thione tautomers are claimed to be more stabilized by solvent effects than the thiol forms, and the 3H,1H tautomer 8b is the most stable. So far, no additional experimental data or ab initio calculations have been reported to confirm these conclusions. 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Thiopurine S methyltransferase Low activity in about 10% of Caucasians and deficient activity in about 0.4%. High incidence of severe adverse events from azathioprine and 6-mercaptopurine in carriers of low activity. 

Thiopurine S-methyltransferase is an enzyme which inactivates the anticancer drug 6-mercaptopurine by S-methylation. 

Although the pathway has not been established, relatively high yields of trimethyltin from inorganic tin have been observed in yeast concomitant with the degradation of butyltin compounds (Errecalde et al. 1995). Exceptionally, methionine transferase may carry out the methylation of Hg in Neurospora crassa (Landner 1971) and thiopurine methyltransferase the methylation of inorganic Se in Escherichia coli (Ranjard et al. 2003). 

Cournoyer B, S Watanabe, A Vivian (1998) A tellurite-resistance genetic determinant from pathogenic pseudomonads encodes a thiopurine methyltransferase evidence of a widely conserved family of methyltransferases. Biochim Biophys Acta 1397 161-168. 

Ranjard L, S Nazaret, B Coumoyer (2003) Freshwater bacteria can methylate selenium through the thiopurine methyltransferase pathway. Appl Environ Microbiol 69 3784-3790. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Thiopurine (6-mercaptopurine) gives rise to three pH-dependent voltam-metric oxidation peaks at the PGE (Table 1) 6S>. The first, least positive peak is an adsorption pre-peak due to the one-electron oxidation of 6-thiopurine (I, Fig. 18) to an adsorbed layer of product, bis (6-purinyl) disulfide (III,... 

Correlations between Electrochemical and Biological Oxidation of 6-Thiopurine... 

In the case of the thiopurines the electrochemical processes do not appear to agree at all with the known biological oxidations. However, again in the case of 6-thiopurine not even a complete picture of the metabolites is available. The electrochemical data indicates that thiopurines are very readily oxidized to disulfides and hence to sulfinic or sulfonic acids. In view of well-known sulfide-disulfide transformations in biological situations (e.g., L-cy-steine to L-cystine), it is not unlikely that part of the metabolic degradation pathway for thiopurines might proceed via reactions of the sulfide moiety. 

Weinshilboum R. Thiopurine pharma-cogenomics clinical and molecular studies of thiopurine methyltransferase. Dmg Metab Dispos 2001 29[4 Pt 2] 601-605. 

Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999 91[23] 2001-2008. 

Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy the thiopurine S-methyltransferase paradigm. Pharm Res 1999 16[3] 342-349. 

Thiopurine S -methyltransferase Drug metabolism SNPs in promoter region, introns and 3 UTR, but not coding region 17... 

Deininger M, Szumlanski CL, Otter-ness DM et al. Purine substrates for human thiopurine methyltransferase. Bio-chem Pharmacol 1994 48 2135-2138. 

Woodson LC, Ames MM, Selassie CD et al. Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 1983 24 471-478. 

McLeod HL, Coulthard S, Thomas AE et al. Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 1999 105 696-700. 

Evans WE, Horner M, Chu YQ et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 1991 119 985-989. 

McBride KL, Gilchrist GS, Smithson WA et al. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inhibited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 2000 22 441-445. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

Otterness D, Szumlanski C, Lennard L et al. Human thiopurine methyltransferase pharmacogenetics gene sequence polymorphisms. Clin Pharmacol Ther 1997 62 60-73. 

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