Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies
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肝外恶性肿瘤小鼠药物转运和代谢的下调
DOI：
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发表时间：
2007
影响因子：
8.8
通讯作者：
Graham R. Robertson
中科院分区：
文献类型：
--
作者：
Raghwa Sharma;M. Kacevska;Roslyn London;Stephen Clarke;Christopher Liddle;Graham R. Robertson
有越来越多的证据表明，全身炎症反应与恶性肿瘤有关，这可能对药物处置和对细胞毒治疗的耐药性产生影响。在携带一些常见肿瘤异种移植瘤的小鼠中，研究了炎症对药物处置的影响。C57BL/6小鼠接种裸鼠移植瘤。从mRNA、蛋白质和功能水平分析肝细胞色素P3A和药物转运蛋白的表达(仅限于细胞色素P3A)。检测血清细胞因子和肝脏急性时相蛋白(APP)的表达。测定肿瘤内多药耐药基因水平。肿瘤移植瘤引起炎症反应，同时抑制肝脏Cyp3a11活性和一些肝脏药物转运蛋白的表达。随着肿瘤的生长，肝脏Cyp3a11基因的表达呈进行性降低。相反，肝组织APP表达和循环白介素6水平升高。此外，多药耐药基因mdr1a在肿瘤内的表达增加与循环IL-6水平之间存在相关性。恶性肿瘤导致肝脏药物处置减少，这与相关的炎症反应有关。减轻炎症可能会改善接受肝代谢化疗药物的患者的临床结果。
There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.
DOI：
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发表时间：
2001-03
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
E. Morgan
通讯作者：
E. Morgan
影响因子：
11.2
作者：
N. Borsellino;A. Belldegrun;B. Bonavida
通讯作者：
N. Borsellino;A. Belldegrun;B. Bonavida