Olsson J M, Schedin S, Teclebrhan H, Eriksson L C, Dallner G
Clinical Research Center, Huddinge Hospital, Karolinska Institutet, Sweden.
Carcinogenesis. 1995 Mar;16(3):599-605. doi: 10.1093/carcin/16.3.599.
Certain enzymes of the mevalonate pathway have been investigated in persistent liver nodules induced in the rat by 2-acetylaminofluorene. In these nodules the dolichol level was increased 5-fold, the ubiquinone-9 content elevated 6-fold and the amount of cholesterol unchanged. Microsomal beta-hydroxy-beta-methylglutaryl-coenzyme A reductase activity was greatly increased compared to control liver tissue, which was also the case for the cytosolic farnesyl pyrophosphate synthase. A significant elevation of all-transgeranylgeranyl pyrophosphate synthase activity in the cytosol was also observed. The branch-point enzyme of microsomal dolichol synthesis, i.e. cis-prenyltransferase, was decreased in the nodules; whereas the activity of squalene synthase, the terminal regulating enzyme of cholesterol synthesis, remained unchanged. The dolichol species in nodular tissue were redistributed towards the longer chain length species. One factor regulating the chain length of the polyisoprene products formed in vitro was shown to be the ratio of the concentrations of isopentenyl pyrophosphate:farnesyl pyrophosphate employed. Other regulatory factors in the terminal steps of this biosynthetic pathway appear to determine the amounts and nature of the final isoprenoid compounds formed in vivo. In contrast to the microsomal trans-prenyltransferase activity, which was unchanged, the activity of nonaprenyl-4-hydroxybenzoate transferase, an enzyme participating in ubiquinone synthesis, was greatly elevated. The alterations observed in the activities of enzymes in the mevalonate pathway can at least partially explain the increased levels of dolichol and ubiquinone and the unchanged level of cholesterol found in liver nodules. It is reasonable to propose that this modified mevalonate metabolism will render nodular cells resistant to certain toxic factors and prone to cell proliferation.
已对2-乙酰氨基芴诱导的大鼠持续性肝结节中甲羟戊酸途径的某些酶进行了研究。在这些结节中，多萜醇水平增加了5倍，泛醌-9含量升高了6倍，而胆固醇含量未变。与对照肝组织相比，微粒体β-羟基-β-甲基戊二酰辅酶A还原酶活性大大增加，胞质法尼基焦磷酸合酶的情况也是如此。还观察到胞质中全反式香叶基香叶基焦磷酸合酶活性显著升高。微粒体多萜醇合成的分支点酶，即顺式异戊烯基转移酶，在结节中减少；而胆固醇合成的末端调节酶角鲨烯合酶的活性保持不变。结节组织中的多萜醇种类向链长更长的种类重新分布。体外形成的聚异戊二烯产物链长的一个调节因素是所用异戊烯基焦磷酸：法尼基焦磷酸的浓度比。该生物合成途径末端步骤中的其他调节因素似乎决定了体内最终类异戊二烯化合物的数量和性质。与未改变的微粒体反式异戊烯基转移酶活性相反，参与泛醌合成的酶九异戊烯基-4-羟基苯甲酸转移酶的活性大大升高。甲羟戊酸途径中酶活性的变化至少可以部分解释肝结节中多萜醇和泛醌水平的升高以及胆固醇水平的不变。有理由提出，这种改变的甲羟戊酸代谢将使结节细胞对某些毒性因子具有抗性并易于细胞增殖。
