title: Evidence that NADPH-dependent methemoglobin reductase and administered riboflavin protect tissues from oxidative injury.
abstract: NADPH-dependent methemoglobin reductase, first detected in erythrocytes sixty years ago, has subsequently been purified and characterized as a methylene blue reductase and a flavin reductase. The reductase plays no role in methemoglobin reduction under normal conditions, but its activity serves as the basis for the treatment of methemoglobinemia with methylene blue or flavin. On-going studies demonstrate that this cytosolic protein is also present in liver and that its primary structure distinguishes it from other known proteins. The bovine erythrocyte reductase tightly binds hemes, porphyrins, and fatty acids with resulting loss of activity. Pyrroloquinoline quinone serves as a high-affinity substrate of the reductase, suggesting that this naturally-occurring compound may be a physiological substrate. The ability of the reductase to catalyze the intracellular reduction of administered riboflavin to dihydroriboflavin suggested that this system might be exploited to protect tissues from oxidative damage. This hypothesis was supported by our finding that dihydroriboflavin reacts rapidly with Fe(IV)O and Fe(V)O oxidation states of hemeproteins, states that have been implicated in tissue damage associated with ischemia and reperfusion. Preliminary studies demonstrate that, as predicted, administration of low concentrations of riboflavin protects isolated rabbit heart from reoxygenation injury, rat lung from injury resulting from systemic activation of complement, and rat brain from damage caused by four hours of ischemia. Data from these animal studies suggest that flavin therapy holds promise in protecting tissue from the oxidative injuries of myocardial infarction, acute lung injury, stroke, and a number of other clinical conditions.
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor 48109-0606.
authors.forename: D E
authors.initials: DE
authors.lastname: Hultquist
authors.forename: F
authors.initials: F
authors.lastname: Xu
authors.forename: K S
authors.initials: KS
authors.lastname: Quandt
authors.forename: M
authors.initials: M
authors.lastname: Shlafer
authors.forename: C P
authors.initials: CP
authors.lastname: Mack
authors.forename: G O
authors.initials: GO
authors.lastname: Till
authors.forename: A
authors.initials: A
authors.lastname: Seekamp
authors.forename: A L
authors.initials: AL
authors.lastname: Betz
authors.forename: S R
authors.initials: SR
authors.lastname: Ennis
mesh_terms: D000818:Animals; D042966:Cytochrome-B(5) Reductase / Q000502:physiology*; D006801:Humans; D007511:Ischemia / Q000473:pathology*; D009249:NADP / Q000502:physiology*; D010100:Oxygen / Q000009:adverse effects*; D015427:Reperfusion Injury / Q000517:prevention & control*; D012256:Riboflavin / Q000494:pharmacology*
chemical_list: D009249:NADP; D042966:Cytochrome-B(5) Reductase; D010100:Oxygen; D012256:Riboflavin