title: In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-(13) C]pyruvate.
abstract: To date, measurements of the activity of aldehyde dehydrogenase-2 (ALDH2), a critical mitochondrial enzyme for the elimination of certain cytotoxic aldehydes in the body and a promising target for drug development, have been largely limited to in vitro methods. Recent advancements in MRS of hyperpolarized (13) C-labeled substrates have provided a method to detect and image in vivo metabolic pathways with signal-to-noise ratio gains greater than 10 000-fold over conventional MRS techniques. However aldehydes, because of their toxicity and short T1 relaxation times, are generally poor targets for such (13) C-labeled studies. In this work, we show that dynamic MRSI of hyperpolarized [1-(13) C]pyruvate and its conversion to [1-(13) C]lactate can provide an indirect in vivo measurement of ALDH2 activity via the concentration of NADH (nicotinamide adenine dinucleotide, reduced form), a co-factor common to both the reduction of pyruvate to lactate and the oxidation of acetaldehyde to acetate. Results from a rat liver ethanol model (n = 9) show that changes in (13) C-lactate labeling following the bolus injection of hyperpolarized pyruvate are highly correlated with changes in ALDH2 activity (R(2) = 0.76).
authors.affiliation: SRI International, Neuroscience Program, Menlo Park, CA, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Josan
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Yen
authors.forename: Ralph
authors.initials: R
authors.lastname: Hurd
authors.forename: Julio
authors.initials: J
authors.lastname: Ferreira
authors.forename: Che-Hong
authors.initials: CH
authors.lastname: Chen
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Adolf
authors.initials: A
authors.lastname: Pfefferbaum
authors.forename: Dirk
authors.initials: D
authors.lastname: Mayer
authors.forename: Daniel
authors.initials: D
authors.lastname: Spielman
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002247:Carbon Isotopes; D004221:Disulfiram / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002247:Carbon Isotopes; D024101:Mitochondrial Proteins; D019289:Pyruvic Acid; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D004221:Disulfiram