阿扎硫嘌呤 ADME
中文名称
通路描述
硫脲类化合物最初于 20 世纪 50 年代初开发用于癌症治疗，6-巯基嘌呤（6MP）是 FDA 批准治疗白血病的第一种硫脲类化合物，其发现仅两年后。阿扎硫嘌呤（AZA）是 6MP 的前药，几年后通过添加硝基咪唑基团开发，以绕过 6MP 因氧化作用在肠细胞中产生的高首过代谢。AZA 是一种硫脲类前药，其药理作用基于释放活性代谢物 6-巯基嘌呤（6MP），后者进一步代谢为药理活性的 6-硫鸟嘌呤核苷酸（6-TGNs）。这些 6-TGNs 通过四种方式发挥细胞毒性作用：1. 将 6-硫鸟苷三磷酸（6TGTP）掺入 RNA；2. 将 6-硫脱氧鸟苷三磷酸（6TdGTP）掺入 DNA；3. 由甲基巯嘌呤核苷酸（如甲基硫鸟苷单磷酸）抑制从头嘌呤合成；4. 6TGTP 抑制 RAC1，诱导激活的 T 细胞凋亡。虽然 AZA 已被替代作为抗肿瘤药物，但它仍作为免疫抑制抗代谢药物有用，用于治疗类风湿关节炎、克罗恩病、溃疡性结肠炎、癌症以及肾移植患者防止排斥反应（Axelrad 等，2016；Tominaga 等，2021）。AZA 代谢的分子步骤描述在此通路中（Cuffari 等，1996；Dubinsky 2004）。简要来说，口服 AZA 迅速转化为 6MP。初始 6MP 代谢通过竞争性的分解代谢（XDH、TPMT）和合成代谢（HPRT）酶途径进行。一旦形成，6-硫苷 5'-单磷酸（6TIMP）由鸟苷酸单磷酸脱氢酶（IMPDH）和鸟苷酸合酶（GMPS）进一步代谢为 6-硫鸟苷 5'-单磷酸（6TGMP）。6TGMP 由其各自的激酶转化为具有药理活性的二聚体和三聚体衍生物。
英文描述
Azathioprine ADME Thiopurines were originally developed for cancer treatment in the early 1950s, with 6-mercaptopurine (6MP) being the first thiopurine approved by the FDA for the treatment of leukaemia, just two years after its discovery. Azathioprine (AZA), a prodrug of 6MP, was developed by the addition of a nitroimidazol group a few years later to bypass the high first-pass metabolism of 6MP due to oxidation in intestinal cells by xanthine oxidase (XDH). AZA is a thiopurine prodrug, and its pharmacological action is based on the release of the active metabolite 6-mercaptopurine (6MP) which is further metabolised to pharmacoligically active 6-thioguanine nucleotides (6-TGNs). These 6-TGNs achieve their cytotoxic effects in one of four ways
1. Incorporation of 6-thioguanosine triphosphate (6TGTP) into RNA
2. Incorporation of 6-thiodeoxyguanosine triphosphate (6TdGTP) into DNA
3. Inhibition of de novo purine synthesis by methylmercaptopurine nucleotides such as methylthioinosine monophosphate (meTIMP)
4. Inhibition of RAC1 by 6TGTP which induces apoptosis in activated T-cells.
While AZA has been supplanted as an antitumour drug, it remains useful as an immunosuppressant antimetabolite drug indicated to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, cancer and to prevent rejection in kidney transplant patients (Axelrad et al. 2016, Tominaga et al. 2021).
The molecular steps of AZA metabolism are described in this pathway (Cuffari et al. 1996, Dubinsky 2004). Briefly, oral AZA is rapidly converted to 6MP. Initial 6MP metabolism occurs along competing catabolic (XDH, TPMT) and anabolic (HPRT) enzymatic pathways. Once formed, 6-thiosine 5â²-monophosphate (6TIMP) is further metabolized by inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthetase (GMPS) to 6-thioguanosine 5â²monophosphate (6TGMP). 6TGMP is then converted to the pharmacologically-active di- and tri- derivatives by their respective kinases.
1. Incorporation of 6-thioguanosine triphosphate (6TGTP) into RNA
2. Incorporation of 6-thiodeoxyguanosine triphosphate (6TdGTP) into DNA
3. Inhibition of de novo purine synthesis by methylmercaptopurine nucleotides such as methylthioinosine monophosphate (meTIMP)
4. Inhibition of RAC1 by 6TGTP which induces apoptosis in activated T-cells.
While AZA has been supplanted as an antitumour drug, it remains useful as an immunosuppressant antimetabolite drug indicated to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, cancer and to prevent rejection in kidney transplant patients (Axelrad et al. 2016, Tominaga et al. 2021).
The molecular steps of AZA metabolism are described in this pathway (Cuffari et al. 1996, Dubinsky 2004). Briefly, oral AZA is rapidly converted to 6MP. Initial 6MP metabolism occurs along competing catabolic (XDH, TPMT) and anabolic (HPRT) enzymatic pathways. Once formed, 6-thiosine 5â²-monophosphate (6TIMP) is further metabolized by inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthetase (GMPS) to 6-thioguanosine 5â²monophosphate (6TGMP). 6TGMP is then converted to the pharmacologically-active di- and tri- derivatives by their respective kinases.
所含基因
23 个基因