In vitro metabolism of cathinone positional isomers: does sex matter?

• Published in: Analytical and bioanalytical chemistry Vol. 415; no. 22; pp. 5403 - 5420
• Main Authors: Che, Peng, Davidson, J. Tyler, Still, Kristina, Kool, Jeroen, Kohler, Isabelle
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2023; Springer; Springer Nature B.V
• Subjects: Alkaloids; Analytical Chemistry; Biochemistry; Biotransformation; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Females; Food Science; Identification and classification; Isomers; Laboratory Medicine; Liquid chromatography; Liver; Males; Mass spectrometry; Mass spectroscopy; Metabolic pathways; Metabolism; Metabolites; Methods; Microsomes; Monitoring/Environmental Analysis; Monoamines; Properties; Public health; Relative abundance; Research Paper; Sex; Toxicology; Xenobiotics; United States; Netherlands; Synthetic cathinones; In vitro metabolism; Sex-specific differences; Positional isomers; Methylmethcathinones
• ISSN: 1618-2642; 1618-2650; 1618-2650
• DOI: 10.1007/s00216-023-04815-3

Synthetic cathinones, one of the most prevalent categories of new psychoactive substances, have been posing a serious threat to public health. Methylmethcathinones (MMCs), notably 3-MMC, have seen an alarming increase in their use in the last decade. The metabolism and toxicology of a large majority of synthetic cathinones, including 3-MMC and 2-MMC, remain unknown. Traditionally, male-derived liver materials have been used as in vitro metabolic incubations to investigate the metabolism of xenobiotics, including MMCs. Therefore, little is known about the metabolism in female-derived in vitro models and the potential sex-specific differences in biotransformation. In this study, the metabolism of 2-MMC, 3-MMC, and 4-MMC was investigated using female rat and human liver microsomal incubations, as well as male rat and human liver microsomal incubations. A total of 25 phase I metabolites of MMCs were detected and tentatively identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Seven sex-specific metabolites were detected exclusively using pooled male rat liver microsomal incubations. In addition, the metabolites generated from the sex-dependent in vitro metabolic incubations that were present in both male and female rat liver microsomal incubations showed differences in relative abundance. Yet, neither sex-specific metabolites nor significant differences in relative abundance were observed from pooled human liver microsomal incubations. This is the first study to report the phase I metabolic pathways of MMCs using in vitro metabolic incubations for both male and female liver microsomes, and the relative abundance of the metabolites observed from each sex. Graphical abstract