Ransom J T
Syntex Discovery Research, Center for Inflammation Research, Palo Alto, California 94304, USA.
Ther Drug Monit. 1995 Dec;17(6):681-4. doi: 10.1097/00007691-199512000-00023.
Mycophenolate mofetil is a prodrug which is rapidly converted to mycophenolic acid (MPA), a potent and reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the de novo purine synthesis pathway, IMPDH is the first of two enzymes responsible for the conversion of inosine monophosphate (IMP) to guanosine monophosphate (GMP), which is normally converted to GDP, GTP, and dGTP. IMPDH is not involved in the salvage pathway of purine biosynthesis. It has been proposed that, since lymphocytes are relatively independent of the salvage pathway of nucleotide biosynthesis, MPA treatment should reduce guanine nucleotide pools in lymphocytes. Measurements show that MPA causes a reduction of GTP and dGTP in lymphocytes but not neutrophils. The consequences of the reduction in guanine nucleotides in lymphocytes, such as the inhibition of DNA synthesis, and GTP-dependent metabolic events, is discussed.
霉酚酸酯是一种前体药物，可迅速转化为霉酚酸（MPA），后者是肌苷单磷酸脱氢酶（IMPDH）的一种强效可逆非竞争性抑制剂。在嘌呤从头合成途径中，IMPDH是负责将肌苷单磷酸（IMP）转化为鸟苷单磷酸（GMP）的两种酶中的第一种，而GMP通常会转化为GDP、GTP和dGTP。IMPDH不参与嘌呤生物合成的补救途径。有人提出，由于淋巴细胞相对独立于核苷酸生物合成的补救途径，MPA治疗应会减少淋巴细胞中的鸟嘌呤核苷酸池。测量结果表明，MPA会导致淋巴细胞中GTP和dGTP减少，但不会导致中性粒细胞中GTP和dGTP减少。本文讨论了淋巴细胞中鸟嘌呤核苷酸减少的后果，如DNA合成抑制和GTP依赖性代谢事件。
