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乳腺癌组织微粒体中CYP3A4、CYP2C9和CYP2B6的表达及异环磷酰胺的代谢转化

CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes.

作者信息

Schmidt R, Baumann F, Knüpfer H, Brauckhoff M, Horn L-C, Schönfelder M, Köhler U, Preiss R

机构信息

Institute of Clinical Pharmacology, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany.

出版信息

Br J Cancer. 2004 Feb 23;90(4):911-6. doi: 10.1038/sj.bjc.6601492.

DOI:10.1038/sj.bjc.6601492
PMID:14970873
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2410158/
Abstract

Ifosfamide is a prodrug that requires bioactivation by cytochrome P450 for antitumour activity. Up to now, little is known, to what extent in addition to the liver the ifosfamide metabolism may occur intratumorally. For this purpose, we investigated the expression of CYP3A4, CYP2C9 and CYP2B6 in breast cancer tissue using Western Blotting. Ifosfamide turnover was determined by detection of metabolites of the ifosfamide 4-hydroxylation and N-dechloroethylation in tumour microsomal incubations using HPLC/UV and LC/MS. The results demonstrate that all mammary tumours (n=11) reveal CYP3A4 expression; contents varied from 0.5 to 63 pmol mg(protein)(-1). CYP2C9 (n=9) was present in all tested breast tumour samples, too, while CYP2B6 (n=10) protein could not be detected. All measured breast cancer microsomes (n=4) showed an ifosfamide N-dechloroethylation capacity in the range from 0.04 to 0.21 pmol min(-1) mg(protein)(-1), while metabolites of the 4-hydroxylation could not be determined. In conclusion, the detected presence of CYP3A4 and CYP2C9 in breast tumours offers the possibility of intratumoral turnover of ifosfamide. For the first time in the literature, we could demonstrate a turnover of ifosfamide by microsomal preparations from human breast cancer tissue. A calculated modulation of intratumoral ifosfamide turnover could considerably influence its therapeutic efficiency.

摘要

异环磷酰胺是一种前体药物，需要通过细胞色素P450进行生物活化才能发挥抗肿瘤活性。到目前为止，除肝脏外，异环磷酰胺在肿瘤内代谢的程度尚不清楚。为此，我们使用蛋白质印迹法研究了乳腺癌组织中CYP3A4、CYP2C9和CYP2B6的表达。通过使用高效液相色谱/紫外检测法（HPLC/UV）和液相色谱/质谱法（LC/MS）检测肿瘤微粒体孵育中异环磷酰胺4-羟基化和N-去氯乙基化的代谢产物，来确定异环磷酰胺的周转率。结果表明，所有乳腺肿瘤（n = 11）均显示CYP3A4表达；含量在0.5至63 pmol mg（蛋白质）-1之间变化。CYP2C9（n = 9）也存在于所有测试的乳腺肿瘤样本中，而未检测到CYP2B6（n = 10）蛋白。所有测量的乳腺癌微粒体（n = 4）显示异环磷酰胺N-去氯乙基化能力在0.04至0.21 pmol min-1 mg（蛋白质）-1范围内，而4-羟基化的代谢产物无法确定。总之，在乳腺肿瘤中检测到CYP3A4和CYP2C9的存在，为异环磷酰胺在肿瘤内的周转提供了可能性。在文献中，我们首次证明了人乳腺癌组织微粒体制剂可使异环磷酰胺发生周转。计算得出的肿瘤内异环磷酰胺周转调节可能会极大地影响其治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/4bc2abb708c2/90-6601492f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/9f617ed2ed84/90-6601492f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/dd316bd8f5b9/90-6601492f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/3d1a09745134/90-6601492f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/71947cd1f616/90-6601492f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/4bc2abb708c2/90-6601492f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/9f617ed2ed84/90-6601492f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/ac30c34b48ce/90-6601492f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/dd316bd8f5b9/90-6601492f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/3d1a09745134/90-6601492f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/71947cd1f616/90-6601492f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d59f/2410158/4bc2abb708c2/90-6601492f6.jpg

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