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Wissenschaftlicher Aufsatz, 2017
4 Seiten, Note: 1
Azathioprine drug has been in clinical use since its discovery in 1957 in which it was used as a chemotherapy drug. It produces a biological metabolite known as 6-mercaptopurine which is a metabolically active form and it acts as an immunosuppressant. In regard to pharmacokinetics of azathioprine, this drug functions by inhibiting purine synthesis in the body leading to the impairment of cellular proliferation because there is lack of adequate DNA molecules for the formation of new cell. In particular, immune cells are prevented from multiplication owing to the inhibition of purine synthesis in the lymphoid tissues. It has been found out that the inhibition of DNA synthesis hinders nucleotide salvage process which ensures continuous production of lymphocytes for immune responses, especially during infections (Desler, Lykke & Rasmussen, 2010). Therefore, this research paper focuses on azathioprine genetic polymorphisms.
From a biological perspective, the mechanism of action for azathioprine encompasses various metabolic pathways, especially in regard to DNA synthesis. Its activity is caused by several metabolites, which are released during azathioprine metabolism. For instance, methyl-thioinosine monophosphate (MeTIMP) is the active metabolite and its effect in the body is to block the functioning of amidophosphoribosyltransferase enzyme which is involved in purine synthesis. On the other hand, Thioguanosine triphosphate (TGTP) blocks the regulation of Bcl-Xl protein through interacting with Rac1 GDP-binding protein, thus compromising the functionality of RNA which is attributable to cellular degradation (Adrianowska et al., 2011).
Clinical uses of azathioprine include the treatment of an array of autoimmune diseases, and it is also used for immunosuppressive therapy following organ transplantation to prevent tissue graft rejection. Some of the immune-related diseases treated with azathioprine are rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and multiple sclerosis. Currently, azathioprine is approved by FDA for clinical use in the treatment of rheumatoid arthritis and inflammatory bowel disease (Acosta et al., 2011).
Despite the potency of azathioprine in treating autoimmune diseases and its use in immunosuppressive therapy, the drug’s mechanism of action has been found to be linked to pertinent genetic variability. It is believed that aspect of azathioprine’s genetic variability has compromised its clinical use in the treatment of an array of autoimmune diseases, which are managed under long-term strategies.
Ordinarily, azathioprine metabolism relies on genetic polymorphism of a number of enzymes inside the body of humans. However, inosine triphosphate pyrophosphatase (ITPA) and thiopurine S-methyltransferase have been identified to be the most significant enzymes involved in the azathioprine’s metabolism. Research shows that genetic polymorphisms are the most principal issues related to the adverse clinical effects associated with azathioprine treatment among different patients, although the trends of genetic polymorphism exhibit ethnic links (Torkamani, 2013).
Currently, thiopurine methyltransferase (TPMP) has been found to have 28 variant alleles. However, only a few of the 28 variant alleles have been identified to have known clinical effects, although most of these alleles are associated with decreased enzyme activity in vitro (Torkamani, 2013).
Some of the most common thiopurine methyltransferase variants are TPM*3A, TPMP*3C, TPMP*3B, TPMP*2 and TPMP*8. TPM*3A cause nonsynonymous coding changes which are directed by exon 10 Y240C and exon 7 A154T variants while TPMP*3C and TPMP*3B have been found to contain exon 10 variant and exon 7 variant, respectively. On the other hand, TPMP*2 and TPMP*8 variants, which are associated with reduced catalytic activity in some patients have been found to be containing A80P which is a nonsynonymous variant (Torkamani, 2013).
It is believed that polymorphism of enzymes catalyzing azathioprine metabolism causes a significant influence on the toxicity and efficacy of AZA treatment. For instance, azathioprine toxicity has been found to be caused by TPMP mutations, which increase the production of active metabolites such as TGN. It is believed that excessive accumulation of TGN increases the risk of myelosuppression (Acosta et al., 2011).
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