KINETICS OF FOLATE METABOLISM

乳房叶酸代谢的生化动力学模型 癌细胞已经被配制并用于研究 黄曲霉毒素抑制嘌呤和嘧啶合成的机制 药物甲氨蝶呤(MTX)。该模型由近两个部分组成 独立的成分，一个解释了多谷氨酰胺 一种是甲氨蝶呤，另一种是各种叶酸 相互转换。正常的叶酸都被认为是高度 大约五谷氨酸水平的谷氨酸。MTX 聚谷氨酰胺组分被成功地用一种 允许谷氨酸化、水解性和药物外排的方案 多聚谷氨酸盐。第二个零部件的模型参数 是从大量的MCF-7细胞株叶酸数据中得出的， 主要由叶酸库浓度组成，通过 在药物处理和非药物处理的细胞中的高效液相色谱，以及 分离酶动力学研究中常数的测定 准备工作。 当应用于无药物的MCF-7细胞时，该模型能够 复制实验叶酸浓度(二氢叶酸 (FH2)，5-甲基-，10-甲酰基，5，10-亚甲基-和 未替换

A biochemical kinetic model of folate metabolism in breast cancer cells has been formulated and used to investigate the mechanisms of inhibition of purine and pyrimidine synthesis by the drug methotrexate (MTX). The model consists of two nearly independent components, one accounting for the polyglutamation of MTX and the other accounting for various folate interconversions. Normal folates are all assummed to be highly glutamated at about the pentaglutamate level. The MTX polyglutamation component was successfully modelled by a scheme allowing for glutamation, hydrolysis, and efflux of drug polyglutamates. Model parameters for the second component were derived from a large body of MCF-7 cell line folate data, consisting principally of folate pool concentrations measured by HPLC in both drug-treated and drug free cells, and rate constants determined in kinetic studies of isolated enzyme preparations. When applied to drug-free MCF-7 cells, the model was capable of reproducing experimental folate concentrations (dihydrofolate (FH2), 5-methyl-, 10-formyl-, 5,10-methylene-, and unsubstituted