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Isozymes of Pyruvate Kinase in Liver and Hepatomas of the Rat¹

The Fels Research Institute and the Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [F. A. F., J. B. S., S. W.], and the Department of Biochemistry, Howard University School of Medicine, Washington, D. C. 20001 [H. P. M.]

Pyruvate kinase (PK) (EC 2.7.1.40) isozymes were assayed in normal rat liver and a series of transplantable rat hepatomas ranging widely in growth rate and degree of differentiation, with the use of gradient elution by chloride ion from columns of DEAE-cellulose. In agreement with other studies, three noninterconvertible forms were found in rat tissues: isozyme I, the major form in adult rat liver; isozyme II, the sole form in heart and skeletal muscle; and isozyme III, the sole form in poorly differentiated hepatomas, the major form in normal kidney and lung, and the minor form in adult liver. In normal adult rat liver, PK I makes up 90% of the total activity at 57 units/g tissue, and is decreased to 30 units/g after a 48-hr fast. Carbohydrate refeeding restores the normal PK I level in 24 hr and increases its activity to twice the normal level after 72 hr. Little or no change occurs in PK III, which remains at 3 to 6 units/g. In regenerating liver after partial hepatectomy, PK I was slightly below the normal fasted level, but PK III at 72 hr had about twice the normal activity. Fetal liver of 19 to 21 days had equal PK I and PK III levels, whereas early fetal liver or whole fetus contained almost entirely PK III.

Although one highly differentiated hepatoma, 9618A, has a PK isozyme pattern similar to that of liver, other well- and highly differentiated hepatomas had much lower total activities than liver, with a preponderance of PK III. In contrast, the rapidly growing, poorly differentiated hepatomas had extremely high total PK activity, virtually all consisting of PK III. These results provide further evidence of a profound alteration of gene expression in hepatomas resulting in the loss of a specific liver-marker isozyme with loss of differentiation and its replacement in poorly differentiated hepatomas by high activities of an isozyme normally very low in the normal liver.

¹ This work was aided by Grants CA-10729, CA-10916, and CA-12226 from the National Cancer Institute, and by Grant BC-74 from the American Cancer Society.

² Part of this work was taken from a thesis submitted to the Graduate Council of Temple University, June 1970, in partial fulfillment of the requirements for the Ph.D. degree. Present address: Department of Clinical Chemistry, Temple University Hospital.

Received 10/23/73. Accepted 3/ 7/74.