Cyclic variations in folate composition and pteroylpolyglutamyl hydrolase (conjugase) activity of the rat uterus

The "free" and "total" folate content and the activity of conjugase (pteroylpolyglutamyl hydrolase) were determined in homogenates of rat uteruses from animals sacrificed at specific stages of the reproductive cycle. Among 47 animals, conjugase activity was approximately twice as great during proestrus as in any other stage (P less than 0.001). A significant increase in total folate content (P less than 0.01) was observed in these animals, associated with a relatively greater increase in the free component than in the polyglutamyl component during proestrus. A similar decline in the ratio of total to free folate was observed (P less than 0.02) in a second group of 43 animals in which conjugase was inactivated even more rapidly than in the first group. Vascular engorgement was excluded as an explanation for the changes observed in proestrus. Since certain polyglutamyl derivatives of folate are potent inhibitors of thymidylate synthetase, the observed shift in ratio between total and free folates could be conducive to enhanced activity of this rate-limiting reaction of cellular proliferation. The data suggest that cycles of uterine cell growth and involution may be mediated through hormonally induced changes in enzymes governing the length of gamma-glutamyl folate chains. It is postulated that the mechanism involves the conversion of metabolic inhibitors into active coenzymes for one-carbon transfer reactions, and vice versa.