Consequences of inhibition of guanine nucleotide synthesis by mycophenolic acid and virazole

Abstract

Mycophenolic acid and virazole are inhibitors of inosinate dehydrogenase and produce growth inhibition and loss of viability in cultured murine lymphoma L5178Y cells. Treatment with 1 muM mycophenolic acid produced the following changes in concentrations of acid-soluble nucleotides: (a) guanosine triphosphate decreased to less than 10% of control within 2 hr; (b) uridine triphosphate and cytidine triphosphate concentrations increased markedly; (c) adenosine triphosphate did not change; (d) deoxyguanosine triphosphate decreased; and (e) thymidine triphosphate increased. DNA synthesis was inhibited by 90% within 2 hr, whereas the incorporation of adenosine into RNA and of leucine into protein were much less affected. Virazole (100 muM) produces similar effects. These biochemical effects of mycophenolic acid, as well as its effects on cell growth, can be prevented by addition of guanylate to the medium. Mycophenolic acid treatment also appears to cause breakdown of high-molecular-weight DNA.