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

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-5178Y/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.
AuthorsA K Tyagi, D C Thake, E McGee, D A Cooney
JournalToxicology (Toxicology) Vol. 21 Issue 1 Pg. 59-69 ( 1981) ISSN: 0300-483X [Print] NETHERLANDS
PMID7281196 (Publication Type: Journal Article)
Chemical References
  • Antibiotics, Antineoplastic
  • alanosine
  • Adenylosuccinate Lyase
  • Peptide Synthases
  • phosphoribosylaminoimidazole-succinocarboxamide synthetase
  • Adenylosuccinate Synthase
  • Alanine
  • Adenylosuccinate Lyase (metabolism)
  • Adenylosuccinate Synthase (metabolism)
  • Alanine (analogs & derivatives, metabolism, toxicity)
  • Animals
  • Antibiotics, Antineoplastic (toxicity)
  • Male
  • Mice
  • Organ Specificity
  • Peptide Synthases (metabolism)
  • Tissue Distribution

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