The Association between the Urinary Excretion of Trimethylselenonium and Trimethylsulfonium in Humans

Abstract

Hydrogen sulfide is a signaling molecule that plays important roles in several physiological processes, and its methylation product trimethylsulfonium (TMS) is a natural constituent of human urine that could serve as a biomarker for hydrogen sulfide. In vitro studies showed that the enzyme indole-ethylamine N-methyltransferase (INMT) is responsible for the production of trimethylsulfonium as well as its selenium analogue trimethylselenonium (TMSe). Marked inter-individual variability in TMSe production is associated with genetic polymorphisms in the INMT gene, but it remains unclear whether these polymorphisms affect substrate specificity or general enzymatic activity. Therefore, we explore the association between the TMS and TMSe production phenotypes. Caucasian volunteers were recruited and grouped according to their TMSe status into “TMSe producers” and “TMSe non-producers”, and morning urine samples were collected over 5 consecutive days from each volunteer. A total of 125 urine samples collected from 25 volunteers (13 TMSe producers and 12 TMSe non-producers) were analyzed for total selenium and total sulfur using inductively coupled plasma mass spectrometry (ICPMS), trimethylselenonium using HPLC/ICPMS, and trimethylsulfonium using HPLC/electrospray ionization—triple quadrupole—mass spectrometry (ESI-QQQ-MS). Although there was no correlation between TMS and TMSe urinary levels within the “TMSe producers” group, the “TMSe producers” had urinary levels of TMS 10-fold higher than those of the “TMSe non-producers” (P < 0.001). This result indicates that stratification according to TMSe status or genotype is crucial for the correct interpretation of urinary TMS as a possible biomarker for hydrogen sulfide body pools.

Scientific opinion on the tolerable upper intake level for selenium

“…TMSe is produced following methylation of hydrogen selenide first to methylselenol (driven by thiopurine S ‐methyltransferase (TPMT)), then to DMSe (driven by either TPMT or indolethylamine N ‐methyltransferase (INMT)) and finally to TMSe (driven by INMT). A genetic polymorphism in the human INMT gene results in the fact that some individuals are not able to excrete TMSe in substantial amounts (TMSe non‐eliminators) (Lajin and Francesconi, 2016 ). It has been suggested that conversion of hydrogen selenide to methylselenol and to DMSe takes place in the liver, while the urinary metabolite TMSe is produced from DMSe in the lungs (Fukumoto et al., 2020 ).…”

“…The excretion of DMSe in breath and TMSe in urine has been proposed to reflect processes that aim at minimising selenium accumulation in the body outside the regulated pool (Burk and Hill, 2015 ). Notably, as described in Section 3.2 , TMSe excretion is influenced by a polymorphism in the INMT gene, which characterises individuals as eliminators or non‐eliminators of TMSe, and eliminators may excrete TMSe in urine at usual dietary selenium intakes (Lajin and Francesconi, 2016 ).…”

Human indole(ethyl)amine-N-methyltransferase (hINMT) catalyzed methylation of tryptamine, dimethylsulfide and dimethylselenide is enhanced under reducing conditions - A comparison between 254C and 254F, two common hINMT variants

“…Elevated levels of these volatile compounds can lead to expiration from the lung and skin, and a garlic-odored breath associated with selenium (Se) toxicity (selenosis) and tellurium toxicity [4–7]. Methylation of DMS, DMSe and DMTe yields the positively charged non volatile trimethylated products trimethylsulfonium (TMS), trimethylselenonium (TMSe) and trimethyltelleronium (TMTe), essential for urinary excretion [8–10]. Recent work has shown that human INMT (hINMT) can methylate dialkylthiols [11].…”

Trimethylsulfonium: a promising new biomarker for hydrogen sulfide?

“…Our results indicated significant inter-individual variability in the production of TMS. Trimethylsulfonium and TMSe are known to be produced by the same enzyme thioether S-methyltransferase (12), which is encoded by the INMT gene, and this gene has been found to be genetically polymorphic, with a strong impact reported on TMSe production (23,24). It is therefore likely that the genetic polymorphisms in the INMT gene can impact the production of TMS and result in significant inter-individual variability.…”