title: Enantioselective depletion of mitochondrial glutathione concentrations by (S)- and (R)-3-hydroxy-4-pentenoate.
abstract: (R,S)-3-Hydroxy-4-pentenoate rapidly and selectively depletes the mitochondrial glutathione pool in rat hepatocytes, but shows little cytotoxicity and does not induce mitochondrial dysfunction [Shan, X., et al. (1993) Chem. Res. Toxicol. 6, 75-81]. The objective of the present studies was to investigate the 3-hydroxybutanoate dehydrogenase-dependent oxidation of (R)- and (S)-3-hydroxy-4-pentenoate and the enantioselectivity of 3-hydroxy-4-pentenoate-induced depletion of mitochondrial glutathione concentrations in isolated rat liver mitochondria and hepatocytes. (S)-3-Hydroxy-4-pentenoate, but not (R)-3-hydroxy-4-pentenoate, was a substrate for 3-hydroxybutanoate dehydrogenase. Incubation of rat liver mitochondria or hepatocytes with (S)-3-hydroxy-4-pentenoate resulted in a time- and concentration-dependent depletion of mitochondrial glutathione concentrations, whereas (R)-3-hydroxy-4-pentenoate produced little depletion. These results show that (S)-3-hydroxy-4-pentenoate is a substrate for 3-hydroxy-butanoate dehydrogenase and is converted to the Michael acceptor 3-oxo-4-pentenoate, which reacts with glutathione and thereby depletes the mitochondrial glutathione pool. (S)-3-Hydroxy-4-pentenoate may find use in the study of mitochondrial glutathione homeostasis and the role of mitochondrial glutathione in cellular protection.
authors.affiliation: Department of Pharmacology, University of Rochester, New York 14642, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hashmi
authors.forename: S
authors.initials: S
authors.lastname: Gräf
authors.forename: M
authors.initials: M
authors.lastname: Braun
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000032:analysis*; D006884:Hydroxybutyrate Dehydrogenase / Q000032:analysis; D008297:Male; D008930:Mitochondria, Liver / Q000737:chemistry* / Q000187:drug effects* / Q000201:enzymology; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism
chemical_list: D010421:Pentanoic Acids; C080194:3-hydroxy-4-pentenoic acid; D006884:Hydroxybutyrate Dehydrogenase; D005978:Glutathione