Arellano M, Malet-Martino M, Martino R, Gires P
Biomedical NMR Group, IMRCP Laboratory, Université Paul Sabatier, Toulouse, France.
Br J Cancer. 1998;77(1):79-86. doi: 10.1038/bjc.1998.12.
We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) body weight. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992, 1994), is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.
我们报告了首次在离体灌注大鼠肝脏（IPRL）和大鼠体内将抗癌药物5-氟尿嘧啶（FU）生物转化为两种新代谢物α-氟-β-羟基丙酸（FHPA）和氟乙酸（FAC）的研究。IPRL用两种剂量的纯FU溶液进行灌注，剂量分别为15或45 mg kg⁻¹体重，大鼠腹腔注射180 mg FU kg⁻¹体重。对IPRL灌注液和大鼠尿液进行的¹⁹F NMR分析表明，存在FU的正常代谢物以及少量的FHPA（分别用15或45 mg FU kg⁻¹体重处理的IPRL灌注液中，FHPA占注射FU的0.4%或0.1%；大鼠尿液中占注射FU的0.08%）和FAC（分别用15或45 mg FU kg⁻¹体重处理的IPRL灌注液中，FAC占注射FU的0.1%或0.03%；大鼠尿液中占注射FU的0.003%）。IPRL还用剂量相当于15 mg FU kg⁻¹体重的16.6 mg kg⁻¹体重的盐酸α-氟-β-丙氨酸（FBAL）溶液进行灌注。在灌注液中检测到少量的FHPA（占注射FBAL的0.2%）和FAC（0.07%），从而证明FHPA和FAC源自FBAL的分解代谢。由于FAC是一种众所周知的心脏毒性毒物，FHPA在高剂量时也具有心脏毒性，FU的心脏毒性可能至少源于两个来源。第一个来源在之前的论文中已有阐述（Lemaire等人，1992年、1994年），即市售FU溶液中存在FU的降解产物，这些降解产物会代谢为FHPA和FAC；它们是在溶解药物所需的碱性介质中随着时间形成的。第二个来源在本研究中得到证实，即FU本身代谢为相同的化合物。
