title: A physiologically based in silico model for trans-2-hexenal detoxification and DNA adduct formation in rat.
abstract: trans-2-Hexenal (2-hexenal) is an α,β-unsaturated aldehyde that occurs naturally in a wide range of fruits, vegetables, and spices. 2-Hexenal as well as other α,β-unsaturated aldehydes that are natural food constituents or flavoring agents may raise a concern for genotoxicity due to the ability of the α,β-unsaturated aldehyde moiety to react with DNA. Controversy remains, however, on whether α,β-unsaturated aldehydes result in significant DNA adduct formation in vivo at realistic dietary exposure. In this study, a rat physiologically based in silico model was developed for 2-hexenal as a model compound to examine the time- and dose-dependent detoxification and DNA adduct formation of this selected α,β-unsaturated aldehyde. The model was developed based on in vitro and literature-derived parameters, and its adequacy was evaluated by comparing predicted DNA adduct formation in the liver of rats exposed to 2-hexenal with reported in vivo data. The model revealed that at an exposure level of 0.04 mg/kg body weight, a value reflecting estimated daily human dietary intake, 2-hexenal is rapidly detoxified predominantly by conjugation with glutathione (GSH) by glutathione S-transferases. At higher dose levels, depletion of GSH results in a shift to 2-hexenal oxidation and reduction as the major pathways for detoxification. The level of DNA adduct formation at current levels of human dietary intake was predicted to be more than 3 orders of magnitude lower than endogenous DNA adduct levels. These results support that rapid detoxification of 2-hexenal reduces the risk arising from 2-hexenal exposure and that at current dietary exposure levels, DNA adduct formation is negligible.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. reiko.kiwamoto@wur.nl
authors.forename: Reiko
authors.initials: R
authors.lastname: Kiwamoto
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.forename: Ans
authors.initials: A
authors.lastname: Punt
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D003198:Computer Simulation; D018736:DNA Adducts; D004260:DNA Repair; D005421:Flavoring Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008658:Inactivation, Metabolic; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D005421:Flavoring Agents; C051750:2-hexenal; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione