Oral S-adenosyl methionine (SAM) mediates disruptions in methyl group metabolism due to retinoic acid therapy and alters neurotransmitter metabolism: implications for major depressive disorder

Abstract

Disruptions in methyl group metabolism have been associated with a number of disease states, including birth defects, cardiovascular disease, and neurological disorders. Therefore, characterization of the factors that regulate folate and methyl group supply is essential for the development of disease treatments and prevention. Glycine N-methyltransferase (GNMT), an enzyme essential to methyl group balance, is markedly increased by retinoic acid treatment. Furthermore, retinoid therapy has been shown to impact neurotransmitter metabolism, thereby contributing to the development of major depressive disorder. Recently, it has been shown that depressed patients have low levels of folate, other B-vitamins, and S-adenosyl methionine (SAM), all compounds essential for maintaining effective methyl group metabolism. The following studies were conducted to further characterize the impact of oral retinoic acid administration, and to investigate the potential prevention of any detrimental effects by administering oral SAM. In the preliminary study (Chapter 2), as expected, GNMT activity was significantly increased in rats receiving all-trans retinoic acid (ATRA). Additionally, whole brain serotonin levels were decreased by 46% in rats receiving ATRA, an effect that was partially attenuated by oral SAM. The experiment was repeated with an improved dosing method, longer duration of treatment, and another form of retinoic acid, 13-cis retinoic acid (13CRA). Retinoic acid was shown to increase liver lipids and triglycerides, decrease hepatic SAM, and mildly elevate serotonin, in contrast to the first experiment. ATRA slightly decreased whole brain dopamine transporter (DAT) and 13CRA slightly decreased whole brain norepinephrine transporter (NET); these effects were not seen in rats that received supplemental SAM. Furthermore, SAM abrogated liver lipid content in rats receiving 13CRA, partially prevented increases in liver triglycerides, and restored hepatic SAM levels in both retinoic acid groups. Rats that received only SAM supplementation had extremely high dopamine, and increased ix norepinephrine. SAM supplementation may be an effective therapy for both the mitigation of retinoic acid-related side effects and the prevention or treatment of major depressive disorder.