Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-beta-alanine conjugate: previously unrecognized role for bile acids in drug conjugation.
Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-beta-alanine conjugate: previously unrecognized role for bile acids in drug conjugation.
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5-氟尿嘧啶代谢为 N-胆酰-2-氟-β-丙氨酸缀合物：以前未认识到胆汁酸在药物缀合中的作用。
DOI：
10.1073/pnas.84.15.5439
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发表时间：
1987
影响因子：
11.1
通讯作者：
Diasio,RB
中科院分区：
文献类型：
--
作者：
Sweeny,DJ;Barnes,S;Heggie,GD;Diasio,RB
最近，我们在癌症患者的胆汁中发现了一种以前未被发现的抗癌药物5-氟尿嘧啶（FUra）代谢物的临床显著水平。在目前的研究中，对这些患者胆汁的再分析表明，存在两种而不是一种以前未被识别的代谢物。用反相高效液相色谱法纯化了主要的未识别代谢物，然后用快速原子轰击质谱法测定了其分子量为497。FUra衍生物与胆汁酸n -胆酰甘氨酸（Mr 465）和n -胆酰牛磺酸（Mr 515）在HPLC保留时间和分子量上的相似性，以及FUra分解产物2-氟- β -丙氨酸与氨基酸甘氨酸和牛磺酸的结构相似性，导致该代谢产物可能是2-氟- β -丙氨酸和胆酸的缀合物的假设。用甘氨酸水解酶对纯化的代谢物进行水解，验证了这一假设，然后用高效液相色谱（HPLC）技术鉴定了2-氟- β -丙氨酸（2-氟- β -丙氨酸），并通过气相色谱（GC）和气相色谱-质谱（GC- ms）鉴定了未共轭的胆酸。此外，化学合成的n -胆酰-2-氟- β -丙氨酸在HPLC和TLC上与纯化的胆道代谢物共色谱。总之，这项研究证明了一个独特的，据我们所知，在人体内的药物代谢途径中，氨基酸药物代谢物与胆酸结合并消除到胆汁中。此外，2-氟- β -丙氨酸与胆汁酸结合的发现可能为通过肝动脉输注氟嘧啶后经常观察到的胆汁淤积机制提供一些见解。
Recently we demonstrated clinically significant levels of a previously unrecognized metabolite of the anticancer drug 5-fluorouracil (FUra) in bile of cancer patients. In the present study, reanalysis of bile from these patients demonstrated the presence of not one but two previously unrecognized metabolites. The major unrecognized metabolite was purified by reversed-phase HPLC, after which its molecular weight was determined by fast-atom-bombardment mass spectrometry to be 497. The similarity in HPLC retention times and molecular weights of this FUra derivative and the bile acids N-cholylglycine (Mr 465) and N-cholyltaurine (Mr 515), along with the structural similarity of the FUra catabolite 2-fluoro-beta-alanine and the amino acids glycine and taurine, led to the hypothesis that this metabolite could be a conjugate of 2-fluoro-beta-alanine and cholic acid. This hypothesis was tested and confirmed by hydrolyzing the purified metabolite by cholylglycine hydrolase after which: 2-fluoro-beta-alanine was demonstrated by using a sensitive HPLC technique capable of resolving all of the known putative FUra metabolites, and unconjugated cholic acid was identified by both GC and GC-MS. Additionally, chemically synthesized N-cholyl-2-fluoro-beta-alanine was shown to cochromatograph on HPLC and TLC with the purified biliary metabolite. In summary, this study demonstrates a unique, so far as we know, pathway of drug metabolism in man in which an amino acid drug metabolite is conjugated with cholic acid and eliminated into the bile. Furthermore, the finding that 2-fluoro-beta-alanine is conjugated to bile acids may provide some insight into the mechanism of cholestasis that is frequently observed after administration of fluoropyrimidine by hepatic arterial infusion.