α-Methyltryptamine (α-MT) Metabolite Profiling in Human Hepatocyte Incubations and Postmortem Urine and Blood
Sara Malaca, Charline Bottinelli, Laurent Fanton, Nathalie Cartiser, Jérémy Carlier, Francesco Paolo Busardò
Metabolites January 6, 2023 DOI: 10.3390/metabo13010092 via OpenAlex
Summary
α-Methyltryptamine (α-MT) is a hallucinogenic and stimulant drug linked to overdose deaths. To identify biomarkers proving its use, metabolites were analyzed in lab-grown human liver cells and in urine and blood from a fatal overdose case. Nine metabolites formed in liver cells, with eight more in urine and five in blood. Transformations included hydroxylation, sulfation, glucuronidation, and acetylation. The liver cell model matched real samples, confirming its usefulness. Recommended urine biomarkers are α-MT, hydroxy-α-MT glucuronide, and two hydroxy-α-MT sulfates; blood biomarkers are α-MT, two hydroxy-α-MT sulfates, and N-acetyl-α-MT. More studies with varied doses are needed.
Study at a glance
| Characteristics | Observational study with in vitro and postmortem analysis Peer reviewed |
|---|---|
| Population | Human hepatocyte incubations from 10 donors and postmortem urine and blood from one α-MT overdose case |
| Keywords | Metabolite Glucuronidation Tryptamine Urine Sulfation |
| Citations | 6 |
| Key finding | Recommended biomarkers for α-MT use are α-MT, hydroxy-α-MT glucuronide, and two hydroxy-α-MT sulfates in urine, and α-MT, two hydroxy-α-MT sulfates, and N-acetyl-α-MT in blood. |
Abstract
α-MT is a hallucinogenic and stimulant tryptamine that was involved in several overdose fatalities in the United States and Europe. Analytical toxicology, and particularly the identification of metabolite biomarkers in biological samples, often is the only way to prove tryptamine use in clinical and forensic caseworks. We aimed to identify optimal α-MT metabolite biomarkers of consumption in humans. We identified α-MT metabolites in 10-donor-pooled human hepatocyte incubations and postmortem urine and blood from an α-MT overdose case using in silico metabolite predictions, liquid chromatography high-resolution-tandem mass spectrometry (LC-HRMS/MS), and software-assisted data mining. Nine metabolites were identified in vitro and eight additional metabolites were found in urine; five metabolites were found in blood. Metabolic transformations were hydroxylation, O-sulfation, O-glucuronidation, N-glucuronidation, and N-acetylation, consistent with the metabolism of structural analogues. The findings in hepatocyte incubations and postmortem samples were consistent, proving the in vitro model suitability. We suggest α-MT, hydroxy-α-MT glucuronide, and two hydroxy-α-MT sulfates as biomarkers of α-MT use in non-hydrolyzed urine; we suggest α-MT, two hydroxy-α-MT sulfates and N-acetyl-α-MT as biomarkers of α-MT use in blood. Further studies on α-MT clinical and forensic caseworks with different doses and routes of administration are necessary to better explore α-MT metabolism.