Parlo R A, Coleman P S
Biochim Biophys Acta. 1986 Apr 29;886(2):169-76. doi: 10.1016/0167-4889(86)90134-5.
Viable tissue slices from rat liver and Morris hepatoma 3924A were compared as to their ability to incorporate carbons from [U-14 C]pyruvate into newly synthesized cholesterol versus CO2. By 4 h, the tumor slice incubation had incorporated over 6-fold more pyruvate carbons into the sterol than into CO2, relative to the normal liver slice incubation, per g tissue protein. However, the presence of the mitochondrial citrate exchange carrier inhibitor 1,2,3-benzenetricarboxylate in the incubation inhibited the formation of [14C]cholesterol, while simultaneously leading to an increase in the rate of 14CO2 production in the tumor. In the normal liver system by contrast, benzenetricarboxylate also inhibited [14C]cholesterol formation, but had hardly any effect on the already high rate of 14CO2 production. The ability of benzenetricarboxylate to inhibit the rapid carbon flux from pyruvate to cholesterol, and to steer the metabolic flow of carbons toward oxidative decarboxylation via the Krebs cycle in whole, viable tumor tissue, indirectly emphasizes the importance of the mitochondrial citrate exchange carrier in supporting the decontrol of cholesterogenesis de novo in tumors by accelerating the supply of lipogenic precursor carbons to the tumor cytosol. These studies may be therefore interpreted as extensions, to the level of whole-cell metabolism, of the concept of a persistent 'truncated' Krebs cycle in the mitochondria of metastatic cancer tissue. This concept states, in part, that a rapid efflux of mitochondrially generated citrate would operate preferentially in tumors, and thus provide carbons continuously to the cytoplasmic compartment where the well-established deregulated pathway of cholesterogenesis occurs (Parlo, R.A. and Coleman, P.S. (1984) J. Biol. Chem. 259, 9997-10003; Coleman, P.S. and Lavietes, B.B. (1981) CRC Crit. Rev. Biochem. 11, 341-393).
将来自大鼠肝脏和莫里斯肝癌3924A的活组织切片，就其将[U-¹⁴C]丙酮酸中的碳掺入新合成胆固醇与二氧化碳的能力进行了比较。到4小时时，相对于正常肝脏切片孵育，每克组织蛋白，肿瘤切片孵育中掺入固醇的丙酮酸碳比掺入二氧化碳的多6倍以上。然而，孵育中存在线粒体柠檬酸交换载体抑制剂1,2,3-苯三甲酸盐会抑制[¹⁴C]胆固醇的形成，同时导致肿瘤中¹⁴CO₂产生速率增加。相比之下，在正常肝脏系统中，苯三甲酸盐也抑制[¹⁴C]胆固醇的形成，但对本就很高的¹⁴CO₂产生速率几乎没有影响。苯三甲酸盐抑制丙酮酸到胆固醇的快速碳通量，并引导碳的代谢流通过整个活肿瘤组织中的克雷布斯循环进行氧化脱羧的能力，间接强调了线粒体柠檬酸交换载体在通过加速向肿瘤细胞质供应生脂前体碳来支持肿瘤中胆固醇从头合成失控方面的重要性。因此，这些研究可被解释为将转移性癌组织线粒体中持续的“截断”克雷布斯循环概念扩展到全细胞代谢水平。这一概念部分指出，线粒体产生的柠檬酸快速外流将优先在肿瘤中起作用，从而持续向细胞质区室提供碳，在那里发生已确定的胆固醇合成失调途径（帕洛，R.A.和科尔曼，P.S.（1984年）《生物化学杂志》259，9997 - 10003；科尔曼，P.S.和拉维特斯，B.B.（1981年）《CRC生物化学评论》11，341 - 393）。
