J. Biol. Chem., Vol. 259, Issue 2, 929-934, Jan, 1984
Stimulation of tyrosine aminotransferase degradation by methylthioinosine
JW Koontz and WD Wicks
Methylthioinosine (MeSno) is a purine nucleoside analog which is cytotoxic
to a number of cultured cell lines including the Reuber H35 hepatoma cells
used in the present studies. It has also been observed to cause a rapid
profound loss of tyrosine aminotransferase activity in H35 cells well
before the onset of any measurable cytotoxicity. The effect is both time
and concentration dependent. MeSno does not acutely inhibit synthesis of
the enzyme as evidenced by the ability of glucocorticoids or cAMP analogs
to induce the enzyme to the same extent in the presence or absence of the
drug. The enzyme in extracts of cells treated with the drug is essentially
identical with the enzyme from extracts of control cells in terms of
thermal stability, immunoprecipitability, and affinities for substrates and
cofactor. Addition of MeSno to cell extracts and mixing experiments
suggests that the thiopurine does not have any direct effect on enzyme
activity. Immunochemical analysis of the rates of synthesis and degradation
of the aminotransferase have shown that the enzyme is degraded
approximately 3-4 times more rapidly in cells treated with the drug than in
control cells. At the same time there is no inhibition of the rate of
synthesis of the enzyme.
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