Biochemical basis for impaired drug metabolism in tumor-bearing rats. Evidence for altered regulation of hepatic microsomal hemeprotein synthesis.
Biochemical basis for impaired drug metabolism in tumor-bearing rats. Evidence for altered regulation of hepatic microsomal hemeprotein synthesis.
复制标题
荷瘤大鼠药物代谢受损的生化基础。
DOI：
10.1016/0006-2952(82)90378-1
复制
发表时间：
1982
影响因子：
5.8
通讯作者：
Ouellette,MA
中科院分区：
文献类型：
--
作者：
Beck,WT;Dedmon,ML;Ouellette,MA
许多药物在肿瘤动物体内的药理作用增强。这显然是由于肝细胞中这些化合物的微粒体代谢的减少，这是由于微粒体中某些酶的活性或细胞色素P-450含量的减少，或两者兼而有之。由于药物代谢受损可能直接影响化疗的结果，因此开始了对这种改变的生化基础的研究。在患有Walker 256实体瘤的雌性Sprague-Dawley大鼠中，通过延长睡眠时间判断戊巴比妥代谢受损。这种影响伴随着微粒体细胞色素P-450含量的降低。用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳法分析肝脏微粒体，结果显示，与正常对照相比，荷瘤动物肝脏微粒体蛋白减少了约53,000道尔顿（考马斯蓝染色）。当给大鼠注射[3H]亮氨酸时，尽管正常大鼠和荷瘤大鼠微粒体蛋白的dpm/100 μg相同，但荷瘤大鼠细胞色素P-450区3H与微粒体蛋白的相关性（~43,000 ~ ~58,000道尔顿）比正常对照组低约40%。这是由于这些微粒体蛋白的合成速率下降，而不是其他微粒体蛋白的合成速率下降。无论是用3,3',5,5'-四甲基联苯胺染色微粒体蛋白，还是用δ-[14C]氨基乙酰丙酸标记微粒体蛋白，结果显示，与正常对照相比，荷瘤大鼠微粒体血红蛋白的总体含量显著降低（通过14C的掺入判断为~70%）。这些观察结果促使研究血红素的表观限速合成酶和降解酶。我们发现，在7天荷瘤大鼠的肝脏中，δ-氨基乙酰丙酸合成酶的活性仅为对照活性的16%；相反，荷瘤大鼠肝微粒体血红素加氧酶活性比正常动物高近8倍。综上所述，这些数据表明，血红素和血红蛋白合成的扰动导致荷瘤大鼠细胞色素P-450含量的降低，并且它们提供了在生长的、可移植的、非肝肿瘤存在时肝微粒体药物代谢减少的部分解释。
The pharmacologie effects of many drugs are enhanced in animals bearing tumors. This apparently stems from a decrease in the microsomal metabolism of these compounds in liver cells, owing to a decrease in either the activities of certain enzymes or in the content of cytochrome P-450 in microsomes, or both. Since impaired drug metabolism may have a direct bearing on the outcome of chemotherapy, a study of the biochemical basis for this alteration was begun. In female Sprague-Dawley rats bearing Walker 256 solid tumors i.m., pentobarbital metabolism was impaired as judged from prolonged sleeping-times. This effect was accompanied by a decrease in the microsomal content of cytochrome P-450. Analysis of hepatic microsomes by sodium dodecylsulfate-polyacrylamide gel electrophoresis revealed that a microsomal protein of ~53,000 daltons was diminished in livers of tumor-bearing animals, when compared to normal controls, as determined by staining with Coomassie Blue. When rats were injected with [3H]leucine, although the dpm/100 μg of microsomal protein were the same for both normal and tumor-bearing rats, ~40% less3H was associated with the microsomal proteins in the cytochrome P-450 region (~43,000 to ~58,000 daltons) of tumor-bearing animals than with those of normal controls. This was attributed to a decrease in the rate of synthesis of these, but not of other, microsomal proteins. Either staining of microsomal proteins with 3,3',5,5'-tetramethyl-benzidine, or labelling of them with δ-[14C]aminolevulinic acid, revealed that the overall content of microsomal hemeproteins of tumor-bearing rats was reduced considerably, when compared to normal controls (~70% as judged by the incorporation of14C). These observations prompted investigations of the apparent rate-limiting synthetic and degradative enzymes of heme. We found that in the livers of 7-day tumor-bearing rats, the activity of δ-aminolevulinic acid synthetase was only 16% of control activity; conversely, the activity of hepatic microsomal heme oxygenase in the tumor-bearing rats was nearly eight-times greater than that of the normal animals. Together, these data indicate that perturbations in heme- and hemeprotein-synthesis cause the reduced content of cytochrome P-450 seen in tumor-bearing rats, and they provide a partial explanation for diminished drug metabolism by hepatic microsomes in the presence of a growing, transplantable, non-hepatic tumor.