Initial rates of [3H]
adenosine diphosphate and [3H]
adenosine triphosphate uptake were measured in mitochondria isolated from normal rat liver, regenerating liver, mouse
hepatoma BW7756, and four Morris
hepatomas (7777, 7800, 7794A, and 16) of varying degrees of
malignancy. Results obtained demonstrate that (a) the apparent Km and Vmax values for
adenosine diphosphate and
adenosine triphosphate uptake are significantly lower in
hepatoma compared to normal or regenerating liver mitochondria, (b) the Vmax values for
adenosine diphosphate uptake correlate with
tumor growth rate, and (c) the Km values for
adenosine triphosphate in both
hepatoma and normal mitochondria are lowered in the presence of added
uncoupling agents; however, the extent of decrease is much less in fast-growing
tumors than in slow-growing
tumors and normal tissues. Studies examining the causes of reduced transport rates in
hepatoma mitochondria showed that they are independent of the mitochondrial energy state and associated with substantially lower levels of the total and exchangeable
adenine nucleotides. Additional studies revealed that transport rates are also dependent on the size of the
tumor from which the mitochondria are isolated. Mitochondria isolated from small
tumors (less than 2 g) had higher transport rates as well as higher levels of exchangeable and total
adenine nucleotides than those isolated from larger
tumors (4 to 6 g). Endogenous inhibitor levels also varied as a function of
tumor size;
free fatty acid levels increased, whereas
acyl coenzyme A levels declined in mitochondria isolated from larger
tumors. These results seem to indicate that, during the progression of
tumor growth, mitochondria are experiencing cellular environmental changes that will affect overall
tumor cell metabolism.