Cytochromes P450 Catalyze the Reduction of α,β-Unsaturated Aldehydes

Department of Biochemistry and Molecular Biology, The University of Louisville School of Medicine , Louisville, KY 40292, USA.
Chemical Research in Toxicology (Impact Factor: 3.53). 08/2011; 24(8):1223-30. DOI: 10.1021/tx200080b
Source: PubMed


The metabolism of α,β-unsaturated aldehydes, e.g., 4-hydroxynonenal, involves oxidation to carboxylic acids, reduction to alcohols, and glutathionylation to eventually form mercapturide conjugates. Recently, we demonstrated that P450s can oxidize aldehydes to carboxylic acids, a reaction previously thought to involve aldehyde dehydrogenase. When recombinant cytochrome P450 3A4 was incubated with 4-hydroxynonenal, O(2), and NADPH, several products were produced, including 1,4-dihydroxynonene (DHN), 4-hydroxy-2-nonenoic acid (HNA), and an unknown metabolite. Several P450s catalyzed the reduction reaction in the order (human) P450 2B6 ≅ P450 3A4 > P450 1A2 > P450 2J2 > (mouse) P450 2c29. Other P450s did not catalyze the reduction reaction (human P450 2E1 and rabbit P450 2B4). Metabolism by isolated rat hepatocytes showed that HNA formation was inhibited by cyanamide, while DHN formation was not affected. Troleandomycin increased HNA production 1.6-fold while inhibiting DHN formation, suggesting that P450 3A11 is a major enzyme involved in rat hepatic clearance of 4-HNE. A fluorescent assay was developed using 9-anthracenealdehyde to measure both reactions. Feeding mice a diet containing t-butylated hydroxyanisole increased the level of both activities with hepatic microsomal fractions but not proportionally. Miconazole (0.5 mM) was a potent inhibitor of these microsomal reduction reactions, while phenytoin and α-naphthoflavone (both at 0.5 mM) were partial inhibitors, suggesting the role of multiple P450 enzymes. The oxidative metabolism of these aldehydes was inhibited >90% in an Ar or CO atmosphere, while the reductive reactions were not greatly affected. These results suggest that P450s are significant catalysts of the reduction of α,β-unsaturated aldehydes in the liver.

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Available from: Russell A Prough, Oct 09, 2015
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    • "Detoxification of 4-HNE is an important process that has been shown to protect against tissue injury and disease progression (Galligan et al., 2012; Hartley et al., 1999; Terneus et al., 2008). Distinct enzymes have been identified that detoxify 4-HNE, including alcohol dehydrogenase, aldehyde dehydrogenase, aldo-keto reductase, alkenal/one oxidoreductase , cytochrome P450's and various glutathione S-transferases (Amunom et al., 2011; Burczynski et al., 2001; Dick et al., 2001; Forman, 2010; Hartley et al., 1995; Srivastava et al., 2000). Although metabolism of 4-HNE has been studied extensively in the liver, much less is known about its metabolism in the lung and brain, and this represents the focus of the present studies. "
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