ALANOSINE TOXICITY IN NOVIKOFF RAT HEPATOMA-CELLS DUE TO INHIBITION OF CONVERSION OF INOSINE MONOPHOSPHATE TO ADENOSINE-MONOPHOSPHATE

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  • 1 January 1976
    • journal article
    • research article
    • Vol. 36  (4) , 1428-1440
Abstract
2-Amino-3-(hydroxynitrosoamino)propionic acid (alanosine), at a concentration as low as 2.7 .mu.M, completely inhibited the incorporation of hypoxanthine into ADP by cultured Novikiff rat hepatoma cells. Alanosine inhibited the 1st step in the conversion of IMP to AMP because IMP, but not adenylosuccinate, accumulates in treated cells. The alanosine inhibition was not prevented by aspartic acid, even at a concentration of 1mM. Alanosine treatment resulted in the inhibition of cell division, DNA synthesis, RNA and protein synthesis (in this order) and a depletion of the cells of ATP. Some of the cells accumulated in late G2 or M, but the remainder were arrested in other stages of the cell cycle. All effects were due to the inhibition of AMP synthesis and the consequent depletion of the ATP pool since they were completely prevented or reversed by addition of adenine, but not hypoxanthine, to the medium. Pyrimidine nucleotide synthesis was not significantly inhibited by alanosine, since the UTP pool was not affected and uridine failed to reverse the cytotoxicity of alanosine. Alanosine also inhibited the transport of aspartic acid, but had a much lower affinity for this transport system than aspartic acid.