El Sayed Y M, Sadée W
Cancer Res. 1983 Sep;43(9):4039-44.
There are two major R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) activation pathways to 5-fluorouracil, one that is mediated by microsomal cytochrome P-450 oxidation at C-5' of the tetrahydrofuran moiety and one that is mediated by soluble enzymes. This report demonstrates that the soluble enzyme pathway proceeds via enzymatic cleavage (possibly hydrolytic) of the N-1--C-2' bond to yield 5-fluorouracil and 4-hydroxybutanal, which is immediately further metabolized to gamma-butyrolactone or gamma-hydroxybutyric acid. The soluble activation pathway was present in liver, small intestine, and brain. Because of the limited distribution of cytochrome P-450 in body tissues and because of the lack of redistribution of 5-fluorouracil via the systemic circulation after ftorafur administration, we propose that the soluble enzyme pathway is at least in part responsible for organ toxicity and possibly antitumor effect. Distinction of the microsomal (C-5') and the soluble enzyme (C-2') activation pathways can be exploited in the design of more selective prodrug analogues.
R,S-1-(四氢-2-呋喃基)-5-氟尿嘧啶（呋氟尿嘧啶）转化为5-氟尿嘧啶有两条主要途径，一条是由微粒体细胞色素P-450在四氢呋喃部分的C-5'位进行氧化介导的，另一条是由可溶性酶介导的。本报告表明，可溶性酶途径是通过N-1-C-2'键的酶促裂解（可能是水解）产生5-氟尿嘧啶和4-羟基丁醛，4-羟基丁醛会立即进一步代谢为γ-丁内酯或γ-羟基丁酸。可溶性激活途径存在于肝脏、小肠和大脑中。由于细胞色素P-450在身体组织中的分布有限，且在给予呋氟尿嘧啶后5-氟尿嘧啶不会通过体循环重新分布，我们认为可溶性酶途径至少部分导致了器官毒性，并且可能与抗肿瘤作用有关。微粒体（C-5'）和可溶性酶（C-2'）激活途径的区分可用于设计更具选择性的前药类似物。
