In preliminary studies we have observed that the activity of methionine synthetase as significantly increased in zinc-deficient rats (ZD) compared to restricted-fed (RF) or ad-libitum-fed controls. Concomitantly, there was: 1) a decreased proportion of methyltetrahydrofolate (methylTHF) in the liver; 2) a reduction in plasma folate levels, and 3) an increased rate of in vivo histidine oxidation. These phenomena represent a complete reversal of what is observed in vitamin B12 deficiency and is currently known as the "methyl trap" theory. In this condition, methionine synthetase activity is inhibited and, as a result, there is increased methyl THF, elevated plasma folate levels, and impaired histidine oxidation. We are calling the altered folate metabolism due to zinc deficiency a "reverse methyl trap" and hypothesize that the activity of methionine synthetase is, as in the "classical "methyl trap", the factor primarily responsible for establishing the steady-state distribution of the various folate coenzymes and for increasing the rate of methyltetrahydrofolate turnover in tissues. We postulate, furthermore, that the increased methionine synthetase activity in zinc deficiency is due either to decreased levels of methionine (or S-adenosylmethionine), or to changes in endocrine function secondary to zinc deficiency. To test the hypothesis, we propose the following specific aims: 1) To determine the rate of methyltetrahydrofolate turnover and the relative distribution and poly-Gamma-glytamyl chain length of various one-carbonsubstituted folates in the liver of zinc-deficient rats; 2) To study the effects of: a) methionine supplementation, b) testosterone injections and c) thyroxine administration on the activities of methionine synthetase, methylenetetrahydrofolate reductase, serine hydroxymethylase, and formiminotransferase in ZD and RF rats. In these same animals we propose to determine also the turnover of methyltetrahydrofolate, the patterns of hepatic folate coenzymes and the rate of histidine oxidation. In addition, to provide identical food intake to both ZD and control groups, we will feed the liquid diets to rats using a gastric tube. This experiment will be carried out particularly in evaluating the effects of testosterone or thyroxine administration on the activities methionine synthetase, and methylenetetrahydrofolate reductase in tube-fed ZD and control rats.