Shepherd A G, Manson M M, Ball H W, McLellan L I
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Carcinogenesis. 2000 Oct;21(10):1827-34. doi: 10.1093/carcin/21.10.1827.
Certain dietary constituents can protect against chemically induced carcinogenesis in rodents. A principal mechanism by which these chemopreventive compounds exert their protective effects is likely to be via induction of carcinogen detoxification. This can be mediated by conjugation with glutathione, which is synthesized by the sequential actions of glutamate-cysteine ligase (GLCL) and glutathione synthetase. We have demonstrated that dietary administration of the naturally occurring chemopreventive agents, ellagic acid, coumarin or alpha-angelicalactone caused an increase in GLCL activity of between approximately 3- and 5-fold in rat liver. Treatment with the synthetic antioxidant ethoxyquin or the classic inducer phenobarbital caused < 2-fold induction of GLCL activity in rat liver, which was not found to be significant. The increases in GLCL activity were accompanied by increases (between 2- and 4-fold) in levels of both the catalytic heavy subunit (GLCLC) and regulatory light subunit (GLCLR). No substantial induction of GLCL was observed in rat kidney. The glutathione S-transferase (GST) subunits A1, A3, A4, A5, P1 and M1 were all found to be inducible in rat liver by most of the agents. The greatest levels of induction were observed for GST P1, following treatment with coumarin (20-fold), alpha-angelicalactone (10-fold) or ellagic acid (6-fold), and GST A5, following treatment with coumarin (7-fold), alpha-angelicalactone (6-fold) and ethoxyquin (6-fold). Glutathione synthetase was induced approximately 1.5-fold by coumarin, alpha-angelicalactone, ellagic acid and ethoxyquin. The expression of glutathione-related enzymes was also examined in preneoplastic lesions induced in rat liver by aflatoxin B(1). The majority of gamma-glutamyltranspeptidase (GGT)-positive preneoplastic foci contained increased levels of GLCLC relative to the surrounding tissue. This was usually found to be accompanied by an increase in GLCLR. Cells in the inner cortex of rat kidney were found to contain the highest levels of both GLCLC and GLCLR. The same cells showed the strongest staining for GGT activity.
某些膳食成分可预防啮齿动物的化学诱导致癌作用。这些化学预防化合物发挥其保护作用的主要机制可能是通过诱导致癌物解毒。这可以通过与谷胱甘肽结合来介导，谷胱甘肽是由谷氨酸 - 半胱氨酸连接酶（GLCL）和谷胱甘肽合成酶的顺序作用合成的。我们已经证明，膳食给予天然存在的化学预防剂鞣花酸、香豆素或α - 当归内酯可使大鼠肝脏中的GLCL活性增加约3至5倍。用合成抗氧化剂乙氧喹或经典诱导剂苯巴比妥处理后，大鼠肝脏中GLCL活性的诱导倍数<2倍，未发现有统计学意义。GLCL活性的增加伴随着催化重亚基（GLCLC）和调节轻亚基（GLCLR）水平的增加（2至4倍）。在大鼠肾脏中未观察到GLCL的大量诱导。谷胱甘肽S - 转移酶（GST）亚基A1、A3、A4、A5、P1和M1均被大多数试剂诱导在大鼠肝脏中表达。在用香豆素（20倍）、α - 当归内酯（10倍）或鞣花酸（6倍）处理后，观察到GST P1的诱导水平最高；在用香豆素（7倍）、α - 当归内酯（6倍）和乙氧喹（6倍）处理后，观察到GST A5的诱导水平最高。香豆素、α - 当归内酯、鞣花酸和乙氧喹可使谷胱甘肽合成酶诱导约1.5倍。还研究了黄曲霉毒素B1诱导的大鼠肝脏癌前病变中谷胱甘肽相关酶的表达。相对于周围组织，大多数γ - 谷氨酰转肽酶（GGT）阳性癌前病灶中GLCLC水平升高。通常发现这伴随着GLCLR的增加。发现大鼠肾脏内皮质中的细胞含有最高水平的GLCLC和GLCLR。相同的细胞显示出最强的GGT活性染色。
