Mutagen-induced resistance to mycophenolic acid in hamster cells can be associated with increased inosine 5'-phosphate dehydrogenase activity.

Abstract

Cell variants resistant to the cytotoxic effect of mycophenolic acid, an inhibitor of IMP dehydrogenase (IMP:NAD+ oxidoreductase, EC 1.2.1.14), were selected by a one-step procedure from Chinese hamster V79 cells. The frequency of these variants was increased in a dose-dependent manner after treatment with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine and after an expression time of 8 days. The degree of resistance in five of the six isolated cell variants was associated with a comparable increase in the specific activity of IMP dehydrogenase, which was 3- to 6-fold higher than that of the parent V79 cells. The IMP dehydrogenase activity from both the variants and the V79 cells had a similar affinity for the substrate IMP with a Km of about 20 microM and a similar response to mycophenolic acid with a Ki of 12-16 nM. It is suggested that cell variants with an altered regulation of IMP dehydrogenase activity may be helpful in studying the control of nucleic acid biosynthesis, cell growth, and carcinogenesis. Mycophenolic acid resistance also may be useful as a marker in short-term assays for the identification of potential chemical carcinogens.