Factors affecting cytochrome P-450 3A activity in cancer patients
Factors affecting cytochrome P-450 3A activity in cancer patients
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DOI：
10.1158/1078-0432.ccr-04-1371
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发表时间：
2004-12-15
影响因子：
11.5
通讯作者：
Sparreboom, A
中科院分区：
文献类型：
--
作者：
Baker, SD;van Schaik, RHN;Sparreboom, A
目的：目的是确定影响癌症患者 CYP3A 活性的人口统计学、生理学和遗传因素。实验设计：共有 134 名患者（62 名女性；年龄范围为 26 至 83 岁）接受了红霉素呼气试验，作为 CYP3A 表型探针。对 CYP3A4（CYP3A4*1B、CYP3A4*6、CYP3A4*17 和 CYP3A4*18）和 CYP3A5（CYP3A5*3C 和 CYP3A5*6）中疑似功能相关的六种基因组 DNA 进行了筛选。结果：CYP3A 活性（AUC（0-40 分钟））在此过程中变化高达 14 倍人口。 CYP3A4 和 CYP3A5 基因中没有变异是 CYP3A 活性的显着预测因子 (P > 0.2954)。在肝转氨酶和碱性磷酸酶同时升高或总胆红素升高的患者中，CYP3A 活性降低了约 50%（P < 0.001）。在多变量分析中，CYP3A 活性不受年龄、性别和体型测量的显着影响 (P > 0.05)，但肝功能与急性期反应物 α-1 酸性糖蛋白的浓度相结合，解释了与 CYP3A 活性总体变异的 18% 相似的情况 (P < 0.001)。 结论：这些数据表明，基线人口统计学、生理学和选择的遗传多态性对 CYP3A 活性的影响较小。癌症患者的表型 CYP3A 活性。需要考虑其他因素，包括炎症标志物 C 反应蛋白，以及同时使用其他药物、食品成分以及对 CYP3A 具有抑制和诱导作用的补充和替代药物，以减少 CYP3A 的变化和抗癌治疗的治疗结果。
Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients.Experimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6).Results: CYP3A activity (AUC(0-40min)) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by similar to50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained similar to18% of overall variation in CYP3A activity (P < 0.001).Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.