Determinants of the toxicity of L-alanosine to various organs of the mouse

Abstract

Toxicologic and biochemical properties of the antitumor antibiotic, alanosine [L-2-amino-3-(N-hydroxy,N-nitrosamino)propionic acid], were studied in mice. The LD₅₀ of L-alanosine (given intraperitoneally) was approximately 2 g/kg; L-5178Y/AR tumor, small intestine, liver, and lung were the tissues more consistently or severely damaged by the drug. L-a5178Y/AR tumor, small intestine, liver, and lung, which were more susceptible to damage by L-alanosine, showed high concentrations of the putative active antimetabolite of L-alanosine, "L-alanosyl-AICOR", and either high concentrations of SAICAR synthetase, which forms this conjugate or low specific activities of adenylosuccinate lyase, the enzyme believed to decompose it. In addition, a low specific activity of the enzyme, adenylosuccinate synthetase, appeared to predispose an organ to the toxicity of alanosine. These data are compatible with the hypothesis that "L-alanosyl-AICOR" is the molecule responsible both for the therapeutic and toxicologic effects of L-alanosine and suggest that it is the dynamic interplay of the synthesizing enzyme, the catabolizing enzyme, and the target enzyme which determines whether this anabolite accumulates to a concentration capable of inflicting cellular damage.