Interaction between retinoids and methyl group metabolism
Methyl group and folate-dependent one-carbon metabolism play in integral role in health and disease. The donation of carbon in the production of nucleic acids from folate coenzymes and the methylation of biological compounds via transmethylation metabolism is important for maintenance of cells and tissues. Disruption of these tightly regulated pathways can result from genetic polymorphisms of key enzyme, nutritional deficiencies, hormonal imbalances, or drug-treatment interactions. Glycine N-methyltransferase (GNMT) is a key protein that regulates the methyl group supply for S-adenosylmethionine-dependent transmethylation reactions. We have shown that retinoid administration increases GNMT activity and protein abundance, thereby leading to the loss of methyl groups. Previous studies used pharmacological doses (30 [mu]mol/kg BW) of various retinoids administered daily for a total of 10 d. Here, we examined the dose- and time-dependent relationship 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 given either 0, 1, 5, 10, 15 or 30 [mu]mol ATRA/kg BW for 10 d. For the time-course study, rats received 30 [mu]mol ATRA/kg BW for 0, 1, 2, 4, or 8 d. A significant increase (105%) in GNMT activity was observed with doses as low as 5 [mu]mol/kg BW, whereas maximal induction (231%) of GNMT activity was achieved at 30 as 5 [mu]mol/kg BW, whereas maximal induction (231%) of GNMT activity was achieved at 30 [mu]mol/kg BW. Induction of hepatic GNMT by ATRA was rapid, exhibiting a 31% increase following 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 to control values. 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.