title: Intracellular Metabolism of α,β-Unsaturated Carbonyl Compounds, Acrolein, Crotonaldehyde and Methyl Vinyl Ketone, Active Toxicants in Cigarette Smoke: Participation of Glutathione Conjugation Ability and Aldehyde-Ketone Sensitive Reductase Activity.
abstract: The major toxicants in cigarette smoke, α,β-unsaturated aldehydes, such as acrolein (ACR) and crotonaldehyde (CA), and α,β-unsaturated ketone, methyl vinyl ketone (MVK), are known to form Michael-type adducts with glutathione (GSH) and consequently cause intracellular GSH depletion, which is involved in cigarette smoke-induced cytotoxicity. We have previously clarified that exposure to cigarette smoke extract (CSE) of a mouse melanoma cell culture medium causes rapid reduction of intracellular GSH levels, and that the GSH-MVK adduct can be detected by LC/MS analysis while the GSH-CA adduct is hardly detected. In the present study, to clarify why the GSH-CA adduct is difficult to detect in the cell medium, we conducted detailed investigation of the structures of the reaction products of ACR, CA, MVK and CSE in the GSH solution or the cell culture medium. The mass spectra indicated that in the presence of the cells, the GSH-CA and GSH-ACR adducts were almost not detected while their corresponding alcohols were detected. On the other hand, both the GSH-MVK adducts and their reduced products were detected. In the absence of the cells, the reaction of GSH with all α,β-unsaturated carbonyls produced only their corresponding adducts. These results show that the GSH adducts of α,β-unsaturated aldehydes, CA and ACR, are quickly reduced by certain intracellular carbonyl reductase(s) and excreted from the cells, unlike the GSH adduct of α,β-unsaturated ketone, MVK. Such a difference in reactivity to the carbonyl reductase might be related to differences in the cytotoxicity of α,β-unsaturated aldehydes and ketones.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University.
authors.forename: Shizuyo
authors.initials: S
authors.lastname: Horiyama
authors.forename: Mayuko
authors.initials: M
authors.lastname: Hatai
authors.forename: Yuta
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Sachiko
authors.initials: S
authors.lastname: Date
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masujima
authors.forename: Chie
authors.initials: C
authors.lastname: Honda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masaru
authors.initials: M
authors.lastname: Kunitomo
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Takayama
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism*; D007659:Ketones / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D012906:Smoke / Q000032:analysis*; D062789:Tobacco Products / Q000032:analysis*; D014407:Tumor Cells, Cultured
chemical_list: D000447:Aldehydes; D007659:Ketones; D012906:Smoke; D010088:Oxidoreductases; D005978:Glutathione