Toxicometabolomics Characterization of Two N1-Sulfonated Dimethyltryptamine Derivatives in Zebrafish Larvae and Human Liver S9 Fractions Using Liquid Chromatography-High-Resolution Mass Spectrometry.

A liquid chromatography–high-resolution mass spectrometry workflow was used to investigate the metabolism of two N1-sulfonated N,N-dimethyltryptamine derivatives, which have potential for both therapeutic use and recreational abuse. Zebrafish larvae and pooled human liver S9 fractions revealed key phase I and phase II biotransformations. Untargeted metabolomics showed significant downregulation of L-threonine associated with compound exposure. These findings advance the understanding of tryptamine metabolism and highlight the value of toxicometabolomics for evaluating novel psychoactive substances.

Study at a glance

Abstract

Introduction: The availability of toxicokinetic data is critical for detecting and monitoring the intake of psychoactive substances. Timely characterization of novel psychoactive substances (NPS) is particularly important to assess their abuse potential and inform public health responses. Methods: Toxicometabolomics offers a powerful approach to characterize xenobiotic metabolism through high-resolution profiling of biochemical transformations. It thus allows the finding of exogenous biomarkers, such as new drug metabolites, and endogenous biomarkers, which could be indications of acute drug ingestions or sample manipulation, as well as offering information on the mode of action of drugs. In this study, we applied a liquid chromatography-high-resolution mass spectrometry workflow to investigate the toxicometabolomics of two N1-sulfonated N,N-dimethyltryptamine derivatives with potential for both therapeutic use and recreational abuse. Results: Zebrafish (Danio rerio), an increasingly valuable model for preclinical pharmacology and toxicology studies, along with pooled human liver S9 fractions were used to elucidate metabolic pathways and identify key phase I and phase II biotransformations. Furthermore, untargeted metabolomics revealed significant downregulation of L-threonine associated with compound exposure. Conclusions: These findings advance the current understanding of tryptamine metabolism and underscore the utility of toxicometabolomics in the analytical evaluation of NPS.