2 research outputs found
A Metabolomics Study of Retrospective Forensic Data from Whole Blood Samples of Humans Exposed to 3,4-Methylenedioxymethamphetamine: A New Approach for Identifying Drug Metabolites and Changes in Metabolism Related to Drug Consumption
The
illicit drug 3,4-methylenedioxymethamphetamine (MDMA) has profound
physiological cerebral, cardiac, and hepatic effects that are reflected
in the blood. Screening of blood for MDMA and other narcotics are
routinely performed in forensics analysis using ultra-performance
liquid chromatography with high-resolution time-of-flight mass spectrometry
(UPLC–HR-TOFMS). The aim of this study was to investigate whether
such UPLC–HR-TOFMS data collected over a two-year period could
be used for untargeted metabolomics to determine MDMA metabolites
as well as endogenous changes related to drug response and toxicology.
Whole blood samples from living Danish drivers’ positive for
MDMA in different concentrations were compared to negative control
samples using various statistical methods. The untargeted identification
of known MDMA metabolites was used to validate the methods. The results
further revealed changes of several acylcarnitines, adenosine monophosphate,
adenosine, inosine, thiomorpholine 3-carboxylate, tryptophan, <i>S</i>-adenosyl-l-homocysteine (SAH), and lysophospatidylcholine
(lysoPC) species in response to MDMA. These endogenous metabolites
could be implicated in an increased energy demand and mechanisms related
to the serotonergic syndrome as well as drug induced neurotoxicity.
The findings showed that it was possible to extract meaningful results
from retrospective UPLC–HR-TOFMS screening data for metabolic
profiling in relation to drug metabolism, endogenous physiological
effects, and toxicology
Untargeted Metabolomics Analysis of ABCC6-Deficient Mice Discloses an Altered Metabolic Liver Profile
Loss-of-function
mutations in the transmembrane ABCC6 transport
protein cause pseudoxanthoma elasticum (PXE), an ectopic, metabolic
mineralization disorder that affects the skin, eye, and vessels. ABCC6
is assumed to mediate efflux of one or several small molecule compounds
from the liver cytosol to the circulation. Untargeted metabolomics
using liquid chromatography−mass spectrometry was employed
to inspect liver cytosolic extracts from mice with targeted disruption
of the <i>Abcc6</i> gene. Absence of the ABCC6 protein induced
an altered profile of metabolites in the liver causing accumulation
of compounds as more features were upregulated than downregulated
in ABCC6-deficient mice. However, no differences of the identified
metabolites in liver could be detected in plasma, whereas urine reflected
some of the changes. Of note, N-acetylated amino acids and pantothenic
acid (vitamin B5), which is involved in acetylation reactions, were
accumulated in the liver. None of the identified metabolites seems
to explain mineralization in extrahepatic tissues, but the present
study now shows that abrogated ABCC6 function does cause alterations
in the metabolic profile of the liver in accordance with PXE being
a metabolic disease originating from liver disturbance. Further studies
of these changes and the further identification of yet unknown metabolites
may help to clarify the liver-related pathomechanism of PXE