Biosynthesis of N,N-dimethyltryptamine (DMT) in a melanoma cell line and its metabolization by peroxidases.

Tryptophan metabolism includes a minor route producing tryptamine and N,N-dimethyltryptamine (DMT), compounds found in very low amounts and considered trace amines. In a melanoma cell line (SK-Mel-147), DMT and its metabolite N,N-dimethyl-N-formyl-kynuramine (DMFK) were identified in cell supernatant. Adding DMT to the culture led to hydroxy-DMT and indole acetic acid after 24 hours. The cells expressed myeloperoxidase (MPO) mRNA and had peroxidase activity. DMT oxidation by peroxidases (horseradish peroxidase, MPO from activated neutrophils) produced DMFK, N,N-dimethyl-kynuramine, and hydroxy-DMT via the common peroxidase cycle. This describes a previously unreported alternative metabolic pathway for DMT in humans, identifying DMT and metabolites in a melanoma cell line.

Study at a glance

Abstract

Tryptophan (TRP) is essential for many physiological processes, and its metabolism changes in some diseases such as infection and cancer. The most studied aspects of TRP metabolism are the kynurenine and serotonin pathways. A minor metabolic route, tryptamine and N,N-dimethyltryptamine (DMT) biosynthesis, has received far less attention, probably because of the very low amounts of these compounds detected only in some tissues, which has led them to be collectively considered as trace amines. In a previous study, we showed a metabolic interrelationship for TRP in melanoma cell lines. Here, we identified DMT and N,N-dimethyl-N-formyl-kynuramine (DMFK) in the supernatant of cultured SK-Mel-147 cells. Furthermore, when we added DMT to the cell culture, we found hydroxy-DMT (OH-DMT) and indole acetic acid (IAA) in the cell supernatant at 24 h. We found that SK-Mel-147 cells expressed mRNA for myeloperoxidase (MPO) and also had peroxidase activity. We further found that DMT oxidation was catalyzed by peroxidases. DMT oxidation by horseradish peroxidase, H2O2 and MPO from PMA-activated neutrophils produced DMFK, N,N-dimethyl-kynuramine (DMK) and OH-DMT. Oxidation of DMT by peroxidases apparently uses the common peroxidase cycle involving the native enzyme, compound I and compound II. In conclusion, this study describes a possible alternative metabolic pathway for DMT involving peroxidases that has not previously been described in humans and identifies DMT and metabolites in a melanoma cell line. The extension of these findings to other cell types and the biological effects of DMT and its metabolites on cell proliferation and function are key questions for future studies.