Metabolism Of 6mercaptopurine And 6thioguanine

Anabolic and catabolic pathways are involved in the metabolism of thiopurines (Fig. 2) (90,91,92). The enzyme hypoxanthine guanine phosphoribosylferase, responsible for bio-activation of thiopurines, converts 6-MP into 6-thioinosine monophosphate,

Thiopurines Mechanism Action

Fig. 2. Metabolic scheme of thiopurine metabolism. 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; 6-MMP, 6-methyl-mercaptopurine; XO, xanthine oxidase; TPMT, thiopurine S-methyltransferase; HPRT, hypoxanthine guanine phosphoribosyl transferase; IMPDH, inosine monophosphate dehydrogenase; GMPS, guanosine monophosphate synthetase; 6-TX, 6-thioxanthine; 6-TIMP, 6-thioinosine 5'-monophosphate; 6-MMPR, 6-methyl-mercaptopurine ribonucleotides; 6-TXMP, 6-thioxanthine monophoshate; 6-TGMP, 6-thioguanosine 5' monophosphate; 6-TGDP, 6-thioguanosine 5' diphosphate; 6-TGTP, 6-thioguanosine 5' triphosphate; 6-MTGN, 6-methyl-thioguanine nucleotides. The different size of some letters of TGDP and TGTP indicates that isolated 6-thioguanosine 5' phosphates are responsible for a particular mode of action (e.g., only TGDP is converted to 2'-deoxy TGDP).

Fig. 2. Metabolic scheme of thiopurine metabolism. 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; 6-MMP, 6-methyl-mercaptopurine; XO, xanthine oxidase; TPMT, thiopurine S-methyltransferase; HPRT, hypoxanthine guanine phosphoribosyl transferase; IMPDH, inosine monophosphate dehydrogenase; GMPS, guanosine monophosphate synthetase; 6-TX, 6-thioxanthine; 6-TIMP, 6-thioinosine 5'-monophosphate; 6-MMPR, 6-methyl-mercaptopurine ribonucleotides; 6-TXMP, 6-thioxanthine monophoshate; 6-TGMP, 6-thioguanosine 5' monophosphate; 6-TGDP, 6-thioguanosine 5' diphosphate; 6-TGTP, 6-thioguanosine 5' triphosphate; 6-MTGN, 6-methyl-thioguanine nucleotides. The different size of some letters of TGDP and TGTP indicates that isolated 6-thioguanosine 5' phosphates are responsible for a particular mode of action (e.g., only TGDP is converted to 2'-deoxy TGDP).

which is metabolized stepwise by several other intracellular enzymes (e.g., inosine monophosphate dehydrogenase, guanosine monophosphate synthetase) into 6-TGN.

6-TGN represents the sum of 6-thioguanosine monophosphate (6-thio-GMP), -diphosphate (6-thio-GDP) and -triphosphate (6-thio-GTP). In contrast, both TPMT and XO are the predominant catabolic enzymes in the metabolism of thiopurines. TPMT catalyses the S-adenosyl-L-methionine dependent S-methylation of 6-MP and its metabolites into 6-methyl-mercaptopurine (6-MMP), 6-methyl-mercaptopurine ri-bonucleotides (6-MMPR) such as 6-methylthioinosine monophosphat (meTIMP), and 6-methyl-thioguanine nucleotides (6-MTGN) (93).

Thiouric acid is formed by XO and is excreted renally. Whereas the cytosolic enzyme TPMT is expressed ubiquitously in humans [e.g., in the intestine, liver, red blood cells (RBC) and white blood cells], XO is not expressed in hematopoietic tissue (94). Therefore, TPMT-dependent methylation is critical in white blood cells, leading to an enhanced cytotoxic effect in patients with low TPMT activity.

6-TGNs have a half-life of approximately one week with large variability (91,92). Several cytotoxic and immunosuppressant mechanisms of thiopurine action have been described (95, 96, 97, 98, 99, 100). However, the major underlying mode of action in treatment of leukemia is suggested to be the incorporation of 6-TGN into DNA via 2'-deoxy-TGDP and into RNA, thereby inhibiting replication, DNA repair mechanisms, and protein synthesis.

The intermediate metabolite, me-TIMP, inhibits the purine de novo synthesis, thus interfering with replication and contributing to the cytotoxic effects of 6-MP (101,102,103). Thus, it becomes clear that thiopurines are likely to function at least as "two-in-one drugs," and that different mechanisms of thiopurine action are associated to various extents with the clinically observed overall treatment effect of thiopurines.

Recently, a novel mechanism was described. In a first approach, Tiede et al. (104) revealed that 6-thio-GTP bound to the GTPase Racl led to a mitochondrial pathway of apoptosis in CD3 and CD28 co-stimulated T-cells. These data are supported by the finding that patients with Crohn's disease responding to azathioprine had an increased rate of apoptotic cells in intestinal lamina propria cells in contrast to non-responders. In a clinical approach, a ratio of > 0.85 for 6-thio-GTP to 6-thio-GDP and 6-TGN levels of > 100 pmol per 8 x 108 RBC (ratio > 0.85: response in 81%; ratio < 0.85: response in 36%) turned out to be predictive of a response in Crohn's disease patients treated with azathioprine (105).

Subsequently, Poppe et al. (106) found that 6-thio-GTP primarily blocked the guano-sine exchange factor Vavl, leading to accumulation of inactive 6-thio-GDP-loaded Racl, because 6-thio-GTP did not inhibit Rac effector coupling. Inhibition of Rac proteins further led to suppression of CD28 lamellipodia formation and interferon-gamma production. In the absence of apoptosis, Vavl blockade leads to suppression of the conjugation of T-cells with antigen-presenting cells. In conclusion, these findings provide an explanation for azathioprine-mediated suppression of T-cell-dependent pathogenic immune responses. However, it is unclear so far whether this mechanism appears to be important for cytotoxicity of 6-MP/6-TG therapy in childhood leukemia.

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