Characterization of primary glutathione conjugates with acrylamide and glycidamide: Toxicokinetic studies in Sprague Dawley rats treated with acrylamide

• Published in: Chemico-biological interactions Vol. 350; p. 109701
• Main Authors: Luo, Yu-Syuan, Long, Tai-Ying, Chiang, Su-Yin, Wu, Kuen-Yuh
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2021
• Subjects: Acrylamide; Acrylamide-glutathione conjugate (AA-GSH); Detoxification; Glycidamide; Glycidamide-glutathione conjugate (GA-GSH); Toxicokinetics; Toxicokinetics; Acrylamide; Glycidamide-glutathione conjugate (GA-GSH); Acrylamide-glutathione conjugate (AA-GSH); Glycidamide; Detoxification
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2021.109701

Acrylamide (AA) is classified as a probable human carcinogen and is ubiquitous in foods processed at high temperatures. The carcinogenicity of AA has been attributed to its active metabolite, glycidamide (GA). Both AA and GA can spontaneously or enzymatically conjugate with glutathione (GSH) to form their corresponding GSH conjugates. Profiling AA-glutathione conjugate (AA-GSH) and GA-glutathione conjugates (2 isomers: GA2-GSH and GA3-GSH) in serum would better illustrate AA detoxification compared with urinary metabolite analysis. However, the lack of AA-, GA2, and GA3-GSH study remains a critical data gap. Our study aimed to investigate the toxicokinetics of AA-, GA2-and GA3-GSH in Sprague Dawley rats treated with 0.1 mg/kg, 1.0 mg/kg, or 5.0 mg/kg AA. Blood samples were collected for LC-MS/MS analysis of the GSH conjugate products. Within 24 h of treatment, we observed rapid formation, elimination, and linear kinetics of AA-, GA2-and GA3-GSH. The ∑GA-GSH AUC/AA-GSH AUC ratios were 0.14–0.29, similar to ∑GA/AA AUC in serum but different from ∑GA/AA-derived urinary mercapturic acids in rodents. Our analysis of AA- and GA-GSHs values represents direct detoxification of AA and GA in vivo. This study advances our understanding of sex and inter-species differences in AA detoxification and may refine the existing kinetic models for a more relevant risk extrapolation. •Successfully investigated the serum TKs of AA-GSH, GA2-GSH, and GA3-GSH in rat.•AA- and GA-GSHs are rapidly formed and eliminated following AA administrations.•AA- and GA-GSHs show linear TKs with the doses relevant to dietary AA exposure.•Glutathione conjugation with GA is more efficient than that with AA.•Characterized the sex differences in serum TKs of AA- and GA-GSHs.