Effects of inhibitors of adenosine triphosphate: L methionine S adenosyltransferase on levels of S adenosyl L methionine and L methionine in normal and malignant mammalian tissues

Low levels of ATP:L methionine S adenosyltransferase (adenosyltransferase, EC 2.5.1.6) have been detected by a sensitive radioactive assay procedure in transplantable neoplasms, including the Walker 256 tumor of the rat, and the Lewis lung tumor and B 16 melanoma of C₅₇ black mice. These enzymatic activities and those of a number of normal rodent tissues are all significantly inhibited by 1 aminocyclopentanecarboxylic acid (cycloleucine) and by L 2 amino 4 hexynoic acid, which are structural and conformational analogues of L methionine. Following single intraperitoneal injections to rats, the plasma cycloleucine levels remain almost constant for at least 96 hr, whereas the L 2 amino 4 hexynoic acid plasma levels fall with a half life of about 60 hr. Both cycloleucine and L 2 amino 4 hexynoic acid are highly concentrated in the Walker 256 tumor, while the acetylenic amino acid is concentrated in the Lewis lung tumor. Administration of pharmacological doses of cycloleucine (5.19 mmoles/kg) or L 2 amino 4 hexynoic acid (2.64 mmoles/kg) elevates plasma and tissue levels of these amino acids in a dose and time dependent manner to concentrations which are probably sufficiently high to achieve significant inhibition of the tissue adenosyltransferases. Mice and rats treated with these adenosyltransferase inhibitors display dramatic elevations of free L methionine levels in all tissues examined (liver, spleen, kidney, brain, plasma, Walker 256 tumor, and Lewis lung tumor). These effects are dose dependent. The level of five other amino acids (isoleucine, leucine, tyrosine, phenylalanine, and valine) in liver or spleen show only minor changes in response to this treatment, except for a doubling of the phenylalanine level in the spleen. Treatment of animals with high doses of other amino acid analogues that do not inhibit the adenosyltransferases (L norvaline, L valine, DL homoserine) had no effect on the L methionine levels. Treatment with pharmacological doses of cycloleucine and L 2 amino 4 hexynoic acid depresses the levels of (-) S adenosyl L methionine (Ado Met) by 20-40% in most normal and malignant tissues (including spleen, kidney, pancreas, brain, adrenal, Walker 256 tumor of rats, and Lewis lung and L1210 tumors of mice). These effects are time and dose dependent. Amino acids (L norvaline, L serine, and L valine) that are not adenosyltransferase inhibitors are without effect on tissue Ado Met concentrations. In contrast to the findings in other tissues, the Ado Met levels of liver are invariably increased following administration of adenosyltransferase inhibitors.