Metabolic Activation of 2-Methylfuran to Acetylacrolein and Its Reactivity toward Cellular Proteins
- 2-Methylfuran (2-MF) is a process-related contaminant found primarily in heat-treated foods, such as coffee or canned food. The oxidative metabolic activation of 2-MF is supposed to follow the pathway established for furan, which is known to generate the highly reactive metabolite butenedial (BDA). In the case of 2-MF, generation of the BDA homologue 3-acetylacrolein (AcA) is to be expected. 2-MF metabolism to AcA was investigated in two model systems: commercial microsomal preparations and primary rat hepatocytes (pRH). To scavenge the generated 2-MF, two model nucleophils, N-acetyl-l-cysteine (AcCys) and N-α-acetyl-l-lysine (AcLys), were used, and the formation of the corresponding adducts was measured in the supernatants. The metabolic activation of 2-MF to AcA was studied using human liver microsomes as well as rat liver microsomes. Incubation of 2-MF in Supersomes allowed to identify the cytochrome P450 isoenzyme primarily responsible for 2-MF. In addition, primary rat hepatocytes were incubated with 2-MF or AcA and AcLys adduct of AcA (N-α-acetyl-l-lysine-acetylacrolein, AcLys-AcA) determined in the cell supernatants by UHPLC-MS/MS. In model experiments, AcA formed adducts with AcCys and AcLys. The structures of both adducts were characterized. For incubations in biological activating systems, CYP 2E1 was found to be a key enzyme for the conversion of 2-MF to AcA in Supersomes. When pRH were incubated with 2-MF and AcA, AcLys-AcA was detected in the cell supernatants in a time- and dose-dependent manner. The results showed that AcA was indeed formed at the cellular level. In contrast to the AcLys-AcA adduct, no N-acetyl-l-cysteine-acetylacrolein (AcCys-AcA) adduct could be detected in pRH. AcA was determined as a reactive metabolite of 2-MF in vitro, and its adduct formation with nucleophilic cellular components was evaluated. The metabolites were characterized, and AcLys-AcA was identified as potential biomarker.
Author: | Verena Schäfer, Simone Stegmüller, Hanna Becker, Elke RichlingORCiD |
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URN: | urn:nbn:de:hbz:386-kluedo-86443 |
ISSN: | 1520-5010 |
Parent Title (English): | Chemical Research in Toxicology |
Publisher: | ACS Publications |
Document Type: | Article |
Language of publication: | English |
Date of Publication (online): | 2024/09/06 |
Year of first Publication: | 2024 |
Publishing Institution: | Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau |
Date of the Publication (Server): | 2025/01/23 |
Issue: | 2024, 37, 11, 1807–1820 |
Page Number: | 14 |
Source: | 10.1021/acs.chemrestox.4c00083 |
Faculties / Organisational entities: | Kaiserslautern - Fachbereich Chemie |
DDC-Cassification: | 5 Naturwissenschaften und Mathematik / 540 Chemie |
Collections: | Open-Access-Publikationsfonds |
Licence (German): | Zweitveröffentlichung |