Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy.
Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy.
复制标题
DOI：
10.1038/sj.bjc.6600494
复制
发表时间：
2002-09-09
影响因子：
8.8
通讯作者：
Agúndez, JAG
中科院分区：
文献类型：
--
作者：
Martínez, C;García-Martín, E;Pizarro, RM;García-Gamito, FJ;Agúndez, JAG
细胞色素 P450 3A 是一种由 CYP3A4 和 CYP3A5 基因产物产生的药物代谢酶活性，参与抗癌药物的灭活。本研究分析了细胞色素 P450 3A 酶在人类结直肠癌中影响细胞色素 P450 3A 底物药物抗癌治疗的潜力。对人类结直肠癌和健康结直肠上皮细胞中的酶活性、变异性和特性以及灭活紫杉醇（紫杉醇）的能力进行了分析。细胞色素 P450 3A 酶活性存在于健康和肿瘤样本中，个体间差异接近 10 倍。硝苯地平氧化活性±s.d.结直肠癌微粒体的浓度为 67.8±36.6 pmol min−1 mg−1。肿瘤酶的 Km (42±8 μM) 与健康结直肠上皮 (36±8 μM) 和人肝酶的 Km 相似。结直肠癌微粒体代谢抗癌药物紫杉醇，平均活性为 3.1±1.2 pmol min−1 mg−1。主要代谢途径由细胞色素P450 3A执行，并被细胞色素P450 3A特异性抑制剂酮康唑抑制，KI值为31nM。这项研究证明了结直肠癌组织中细胞色素 P450 3A 依赖性代谢的发生。代谢活性赋予癌细胞灭活细胞色素 P450 3A 底物的能力，并可能调节肿瘤对抗癌药物的敏感性。英国癌症杂志 (2002) 87, 681–686。 doi:10.1038/sj.bjc.6600494 www.bjcancer.com © 2002 英国癌症研究中心
Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6 pmol min−1 mg−1. The Km of the tumoral enzyme (42±8 μM) is similar to that in healthy colorectal epithelium (36±8 μM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2 pmol min−1 mg−1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs. British Journal of Cancer (2002) 87, 681–686. doi:10.1038/sj.bjc.6600494 www.bjcancer.com © 2002 Cancer Research UK
登录
查看更多内容
DOI：
10.1097/00008571-199410000-00003
发表时间：
1994-10-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
KOLARS, JC;LOWN, KS;WATKINS, PB
通讯作者：
WATKINS, PB
DOI：
10.1097/00008571-200107000-00008
发表时间：
2001-07-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Eiselt, R;Domanski, TL;Wojnowski, L
通讯作者：
Wojnowski, L
影响因子：
29.4
作者：
Fontana, RJ;Lown, KS;Watkins, PB
通讯作者：
Watkins, PB
影响因子：
3.4
作者：
Sandström, R;Knutson, TW;Lennernäs, H
通讯作者：
Lennernäs, H
影响因子：
6.7
作者：
GARCIAAGUNDEZ, JA;LUENGO, A;BENITEZ, J
通讯作者：
BENITEZ, J