THE RELATION OF FOLIC ACID REDUCTASE TO AMINOPTERIN TOXICITY

¹ Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York

Mice were given a lethal dose of aminopterin 1 hour after a protective injection of folic acid. Liver folic acid reductase activity was reduced to 4% of normal at 24 hours, remained so through the seventh day and returned to normal by the fourteenth day. The activity of folic acid reductase in intestinal mucosa was 6% of normal at 24 hours, returned to 40% by 48 hours and to normal by the fourteenth day. Thus, during the period between the fourth and the seventh day, when restoration of the protective capacity of folic acid occurs, folic acid reductase activity has reappeared in intestinal mucosa but is still negligible in liver.

In both tissues, the sum of drug and residual enzyme content after 24 hours was equal to the drug-combining capacity of the enzyme in normal tissues. The drug was lost from intestinal mucosa in an exponential manner with a half-life of about 60 hours. Drug loss from liver could be described by two exponential processes, one with a half-time of 60 hours and one of 90 days.

It is suggested that folic acid reductase activity is essential for rapidly dividing tissues and that its uncompensated inhibition is responsible for the toxicity of these drugs to normal and neoplastic tissues.

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