Bioactivation of capecitabine in human liver:: Involvement of the cytosolic enzyme on 5′-deoxy-5-fluorocytidine formation
Bioactivation of capecitabine in human liver:: Involvement of the cytosolic enzyme on 5′-deoxy-5-fluorocytidine formation
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DOI：
10.1124/dmd.32.7.762
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发表时间：
2004-07-01
影响因子：
3.9
通讯作者：
Yokoi, T
中科院分区：
文献类型：
--
作者：
Tabata, T;Katoh, M;Yokoi, T
卡培他滨是一种抗癌前药，被认为是通过三种酶生物转化为活性的5-氟尿嘧啶（5-FU）。口服卡培他滨后，首先通过羧化酯酶（CES）代谢为5′-脱氧-5-氟胞苷（5′-DFCR），然后通过胞苷脱氨酶将5′-DFCR转化为5′-脱氧-5-氟脲（5′-DFUR）。5'-DFUR被胸苷磷酸化酶激活为5- fu。虽然人类肝脏中表达了高活性的药物代谢酶，但肝脏在卡培他滨代谢中的作用尚不完全清楚。本研究在体外研究了卡培他滨在人肝脏中的代谢。在二氢嘧啶脱氢酶抑制剂5-氯-2,4-二羟基吡啶存在下，研究了卡培他滨在人肝脏S9、微粒体和细胞质中形成5'-DFCR、5'-DFUR和5- fu。5'-DFCR、5'-DFUR和5- fu分别由卡培他滨在细胞质中和微粒体与细胞质结合形成。在微粒体中仅检测到5'-DFCR形成。细胞质溶胶单独和与微粒体联合催化5-FU形成的表观K-m和V-max值分别为8.1 mM和106.5 pmol/min/mg蛋白，4.0 mM和64.0 pmol/min/mg蛋白。在14个人类肝脏样本中，微粒体和细胞质中5'- dfcr形成的个体间差异分别为8.3倍和12.3倍。卡培他滨似乎在人肝脏中代谢为5-FU。5'-DFCR的形成在细胞质中表现出很大的个体间差异，尽管CES位于人类肝脏的微粒体中。在目前的研究中，已经明确了胞质酶在5'-DFCR的形成中是重要的，就像CES一样。
Capecitabine, an anticancer prodrug, is thought to be biotransformed into active 5-fluorouracil (5-FU) by three enzymes. After oral administration, capecitabine is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase (CES), then 5'-DFCR is converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase. 5'-DFUR is activated to 5-FU by thymidine phosphorylase. Although high activities of drug metabolizing enzymes are expressed in human liver, the involvement of the liver in capecitabine metabolism is not fully understood. In this study, the metabolism of capecitabine in human liver was investigated in vitro. 5'-DFCR, 5'-DFUR, and 5-FU formation from capecitabine were investigated in human liver S9, microsomes, and cytosol in the presence of the inhibitor of dihydropyrimidine dehydrogenase, 5-chloro-2,4-dihydroxypyridine. 5'-DFCR, 5'-DFUR, and 5-FU were formed from capecitabine in cytosol and in the combination of microsomes and cytosol. Only 5'-DFCR formation was detected in microsomes. The apparent K-m and V-max values of 5-FU formation catalyzed by cytosol alone and in combination with microsomes were 8.1 mM and 106.5 pmol/min/mg protein, and 4.0 mM and 64.0 pmol/min/mg protein, respectively. The interindividual variability in 5'-DFCR formation in microsomes and cytosol among 14 human liver samples was 8.3- and 12.3-fold, respectively. Capecitabine seems to be metabolized to 5-FU in human liver. 5'-DFCR formation was exhibited in cytosol with large interindividual variability, although CES is located in microsomes in human liver. In the present study, it has been clarified that the cytosolic enzyme would be important in 5'-DFCR formation, as is CES.