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

Tyagi, Anil K. ; Thake, Daryl C. ; Mcgee, Ellen ; Cooney, David A. (1981) Determinants of the toxicity of L-alanosine to various organs of the mouse Toxicology, 21 (1). pp. 59-69. ISSN 0300-483X

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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.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
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Deposited On:12 Aug 2011 07:08
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