Metabolism of selenite to selenosugar and trimethylselenonium in vivo: tissue dependency and requirement for S-adenosylmethionine-dependent methylation☆ Matthew I. Jackson a, ⁎, Kristoffer Lunøe b , Charlotte Gabel-Jensen b , Bente Gammelgaard b , Gerald F. Combs Jr. a a Grand Forks Human Nutrition Research Center; ARS-USDA, North Dakota, USA b Department of Pharmacy, University of Copenhagen, Denmark Received 21 September 2012; received in revised form 18 April 2013; accepted 18 April 2013 Abstract Impaired S-adenosylmethionine (SAM)-dependent transmethylation and methylation capacity feature in diseases related to obesity or aging, and selenium (Se) metabolism is altered in these states. We tested the hypothesis that SAM metabolism is required for methylation and excretion of Se in a rat model. Four hours after selenite and periodate-oxidized adenosine (POA; an inhibitor of SAM metabolism) were administered, circulating markers of single-carbon status were unchanged, except for decreased circulating phosphatidylcholine (Pb.05). In contrast, liver and kidney SAM and S-adenosylhomocysteine were elevated (Pb.05 for all). Concentrations of total Se were significantly elevated in both liver (Pb.001) and kidney (Pb.01), however the degree of accumulation in liver was significantly greater than that of kidney (Pb.05). Red blood cell Se levels were decreased (P=.01). Trimethylselenonium levels were decreased in liver and kidney (P=.001 for both tissues) and Se-methyl-N-acetylselenohexosamine selenosugar was decreased in liver (P=.001). Urinary output of both trimethylselenonium (P=.001) and selenosugar (P=.01) was decreased as well. Trimethylselenonium production is more inhibited by POA than is selenosugar production (Pb.05). This work indicates that low molecular weight Se metabolism requires SAM-dependent methylation, and disrupting the conversion of SAM to S-adenosylhomocysteine prevents conversion of selenite and intermediate metabolites to final excretory forms, suggesting implications for selenium supplementation under conditions where transmethylation is suboptimal, such as in the case of obese or aging individuals. Published by Elsevier Inc. Keywords: Selenium; Selenite; Selenosugar; Trimethylselenonium; Methylation; Liver; S-adenosylhomocysteine; S-adenosylmethionine; Cancer 1. Introduction Dietary selenium (Se) undergoes non-specific incorporation of selenomethionine (SeMET) in place of methionine during general protein synthesis [1,2] as well as co-translational incorporation into selenoproteins as selenocysteine [3,4]; selenoproteins fulfill diverse, essential biological roles [5–8], and play a role in the anti-cancer activity of Se [9]. Food forms of Se, are also metabolized by reduction and methylation [10,11] to various low molecular weight species including trimethylselenonium ion (TMSe + ), Se-methyl-N-acetylse- lenohexosamine (Se-SUG) and the seleno-amino acids Se-methylse- lenocysteine (MeSeCys) and SeMET. The oxidation state of low molecular weight Se determines its potential for reacting with regulatory cysteine residues in signaling proteins [12], while methylation state imparts hydrophobicity to affect membrane accessibility and prevent further redox cycling [13]. Excess Se can be eliminated in urine after methylation-dependent metabolism to either TMSe + [14,15] or a series of Se-SUG species which comprise the major urinary metabolites of Se in humans [16,17] (Fig. 1). Low molecular weight Se redox cycles to generate reactive oxygen species [18], induces apoptosis [19], covalently modifies thiols [20], alters cell cycle progression [21,22] and protects against the toxic effects of certain chemotherapeutics through maintenance of circadian rhythm [23]. The anticancer activity of Se [24–26] at supranutritional levels appears to be due to the action of low molecular weight, methylated Se-metabolites [27,28]. Individuals vary in their capacity to transform ingested Se to methylated species [29,30]. Genetic, sex and physio- logical factors, account for differences in selenoprotein expres- sion [31–34], but since little is known about the factors influencing inter-individual differences in metabolism of low molecular weight Se it is of interest to elucidate these determinants in vivo. Portions of the whole-body Se pool existing in protein and low molecular weight form are metabolically exchangeable with selenite experimentally administered by injection in both human subjects and rat models [35]. This metabolic pool of Se is termed the “selenite- exchangeable pool” [36–38]. The selenite-exchangeable pool is correlated with total body Se in vivo [39,40], although it can be perturbed in vivo by nutritional supplementation with the reducing agent ascorbic acid [41]. We tested the hypothesis that impairment of S-adenosylmethionine (SAM) dependent methylation decreases metabolism of the selenite-exchangeable pool to low molecular Available online at www.sciencedirect.com ScienceDirect Journal of Nutritional Biochemistry 24 (2013) 2023 – 2030 ☆ Conflict of Interest Statement: All authors state that they have no competing financial or commercial interests. ⁎ Corresponding author. Current institution: Hill's Pet Nutrition 1035 NE 43rd St, Topeka, KS 66617, USA. Tel.: +785 286 8639. E-mail address: matthew_jackson@hillspet.com (M.I. Jackson). 0955-2863/$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jnutbio.2013.04.007