All-trans-retinoic acid rapidly induces glycine N-methyltransferase in a dose-dependent manner and reduces circulating methionine and homocysteine levels in rats

Abstract

Glycine N-methyltransferase (GNMT) regulates the methyl group supply for S-adenosylmethionine-dependent transmethylation reactions. Retinoids have been shown to perturb methyl group metabolism by increasing the abundance and activity of GNMT, thereby leading to the loss of methyl groups. Previous studies used pharmacologic doses (30 micro mol/kg body weight) of various retinoids administered daily for a total of 10 d. Here, we examined the dose- and time-dependent relationships between all-trans-retinoic acid (ATRA) administration and induction of GNMT, as well as determining additional indices of methyl group and folate metabolism. For the dose-response study, rats were administered 0, 1, 5, 10, 15 or 30 micro mol ATRA/kg body weight for 10 d. For the time-course study, rats were given 30 micromol ATRA/kg body weight for 0, 1, 2, 4, or 8 d. A significant increase (105%) in GNMT activity was observed with doses as low as 5 micromol/kg body weight, whereas maximal induction (231%) of GNMT activity was achieved at 30 micromol/kg body weight. Induction of hepatic GNMT by ATRA was rapid, exhibiting a 31% increase after a single dose (1 d) and achieving maximal induction (95%) after 4 d. Plasma methionine and homocysteine concentrations were decreased 42 and 53%, respectively, in ATRA-treated rats compared with controls. In support of this finding, the hepatic activity of methionine synthase, the folate-dependent enzyme required for homocysteine remethylation, was elevated 40% in ATRA-treated rats. This work demonstrates that ATRA administration exerts a rapid effect on hepatic methyl group, folate and homocysteine metabolism at doses that are within the therapeutic range used by humans.