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).