Abstract |
Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of prodrugs widely used to treat bacterial and trypanosome infections, but despite relative specificity, 5-nitrofurans often cause serious toxic side effects in people. Here, we use yeast and zebrafish, as well as human in vitro systems, to assess the biological activity of 5-nitrofurans, and we identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5-nitrofuran anti-trypanosome prodrug, is dependent on zebrafish Aldh2 and is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5-nitrofuran treatment.
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Authors | Linna Zhou, Hironori Ishizaki, Michaela Spitzer, Kerrie L Taylor, Nicholas D Temperley, Stephen L Johnson, Paul Brear, Philippe Gautier, Zhiqiang Zeng, Amy Mitchell, Vikram Narayan, Ewan M McNeil, David W Melton, Terry K Smith, Mike Tyers, Nicholas J Westwood, E Elizabeth Patton |
Journal | Chemistry & biology
(Chem Biol)
Vol. 19
Issue 7
Pg. 883-92
(Jul 27 2012)
ISSN: 1879-1301 [Electronic] United States |
PMID | 22840776
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier Ltd. All rights reserved. |
Chemical References |
- Nitrofurans
- Recombinant Proteins
- ALDH2 protein, human
- Aldehyde Dehydrogenase
- Aldehyde Dehydrogenase, Mitochondrial
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Topics |
- Aldehyde Dehydrogenase
(metabolism)
- Aldehyde Dehydrogenase, Mitochondrial
- Animals
- Dose-Response Relationship, Drug
- Humans
- Melanocytes
(drug effects)
- Models, Molecular
- Molecular Structure
- Nitrofurans
(chemistry, pharmacology)
- Recombinant Proteins
(metabolism)
- Saccharomyces cerevisiae
(drug effects, metabolism)
- Species Specificity
- Structure-Activity Relationship
- Zebrafish
(embryology)
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