Aldehyde Oxidase Importance In Vivo in Xenobiotic Metabolism: Imidacloprid Nitroreduction in Mice
Abstract
Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several examples of biological oxidations mediated by the bicarbonate anion, in particular through interactions with peroxynitrite, have been reported.
“Several examples of biological oxidations mediated by the bicarbonate anion, in particular through interactions with peroxynitrite, have been reported in the literature [e.g., (46, 635, 918, 1056)].”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [918]
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
Guide for the Care and Use of Laboratory Animals: Eighth Edition
(2011) · doi:10.17226/12910 · Cited by 16,199 · see citing works
The 1996 Guide for the Care and Use of Laboratory Animals
Clark, J. D., Gebhart, G. F., Gonder, J. C., Keeling, M. E., & Kohn, D. F. (1997) · ILAR Journal · doi:10.1093/ilar.38.1.41 · Cited by 4,420 · see citing works
Overview of the Status and Global Strategy for Neonicotinoids
Jeschke, P., Nauen, R., Schindler, M., & Elbert, A. (2011) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf101303g · Cited by 1,867 · see citing works
Guide for the Care and Use of Laboratory Animals (8th edn)
Albus, U. (2012) · Laboratory Animals · doi:10.1258/la.2012.150312 · Cited by 1,706 · see citing works
Neonicotinoid insecticide toxicology: mechanisms of selective action.
Tomizawa, M., & Casida, J. (2005) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095930 · Cited by 1,689 · see citing works
Self-citationTomizawa, M., & Casida, J. (2003) · Annual Review of Entomology · doi:10.1146/annurev.ento.48.091801.112731 · Cited by 931 · see citing works
Self-citationAn integrative approach to ortholog prediction for disease-focused and other functional studies
Hu, Y., Flockhart, I., Vinayagam, A., Bergwitz, C., Berger, B., Perrimon, N., & Mohr, S. E. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-357 · Cited by 801 · see citing works
たんぱく質‐色素結合の原理を用いるμg量のたんぱく質の定量のための迅速,高感度法
Bradford, M. M. (1976) · Analytical Biochemistry · Cited by 752 · see citing works
Aldehyde Oxidase: An Enzyme of Emerging Importance in Drug Discovery
Pryde, D. C., Dalvie, D., Hu, Q., Jones, P., Obach, R. S., & Tran, T.-D. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100888d · Cited by 346 · see citing works
Progress in Medicinal Chemistry.
(1963) · doi:10.1021/jm00342a061 · Cited by 234 · see citing works
Human Liver Aldehyde Oxidase: Inhibition by 239 Drugs
Obach, R. S., Huynh, P. T., Allen, M. C., & Beedham, C. (2003) · The Journal of Clinical Pharmacology · doi:10.1177/0091270003260336 · Cited by 224 · see citing works
Drug-Metabolizing Ability of Molybdenum Hydroxylases
Kitamura, S., Sugihara, K., & Ohta, S. (2006) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.21.83 · Cited by 216 · see citing works
Nauen, R., Tietjen, K., Wagner, K., et al. (1998) · Pesticide Science · doi:10.1002/(sici)1096-9063(199801)52:1 · Cited by 211 · see citing works
Unique and Common Metabolites of Thiamethoxam, Clothianidin, and Dinotefuran in Mice
Ford, K. A., & Casida, J. E. (2006) · Chemical Research in Toxicology · doi:10.1021/tx0601859 · Cited by 205 · see citing works
Self-citationChao, S. L., & Casida, J. E. (1997) · Pesticide Biochemistry and Physiology · doi:10.1006/pest.1997.2284 · Cited by 192 · see citing works
Self-citationMammalian aldehyde oxidases: genetics, evolution and biochemistry
Garattini, E., Fratelli, M., & Terao, M. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7398-y · Cited by 188 · see citing works
Comparative Metabolism and Pharmacokinetics of Seven Neonicotinoid Insecticides in Spinach
Ford, K. A., & Casida, J. E. (2008) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf8020909 · Cited by 178 · see citing works
Self-citationFord, K. A., & Casida, J. E. (2006) · Chemical Research in Toxicology · doi:10.1021/tx0600696 · Cited by 175 · see citing works
Self-citationPOTENT INHIBITION OF HUMAN LIVER ALDEHYDE OXIDASE BY RALOXIFENE
Obach, R. S. (2004) · Drug Metabolism and Disposition · doi:10.1124/dmd.32.1.89 · Cited by 168 · see citing works
Schulz-Jander, D., & Casida, J. E. (2002) · Toxicology Letters · doi:10.1016/s0378-4274(02)00068-1 · Cited by 164 · see citing works
Self-citation3 Molybdenum Hydroxylases: Biological Distribution and Substrate-Inhibitor Specificity
Beedham, C. (1987) · Progress in medicinal chemistry · doi:10.1016/s0079-6468(08)70420-x · Cited by 129 · see citing works
Enzymes and Inhibitors in Neonicotinoid Insecticide Metabolism
Shi, X., Dick, R. A., Ford, K. A., et al. (2009) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf900250f · Cited by 95 · see citing works
Identification of Aldehyde Oxidase as the Neonicotinoid Nitroreductase
Dick, R. A., Kanne, D. B., & Casida, J. E. (2005) · Chemical Research in Toxicology · doi:10.1021/tx049737i · Cited by 85 · see citing works
Self-citationHydralazine: A potent inhibitor of aldehyde oxidase activity in vitro and in vivo
Johnson, C., Stubley-Beedham, C., Godfrey, J., et al. (1985) · Biochemical Pharmacology · doi:10.1016/0006-2952(85)90280-1 · Cited by 75 · see citing works
Schulz-Jander, D., Leimkuehler, W. M., & Casida, J. E. (2002) · Chemical Research in Toxicology · doi:10.1021/tx0200360 · Cited by 68 · see citing works
Self-citationHemingway, J., Coleman, M. M., PATON, M. G., et al. (2000) · Insect Molecular Biology · doi:10.1046/j.1365-2583.2000.00160.x · Cited by 55 · see citing works
Regulation and Biochemistry of Mouse Molybdo-flavoenzymes
Vilà, R., Kurosaki, M., Barzago, M. M., Kolek, M., Bastone, A., Colombo, L., Salmona, M., Terao, M., & Garattini, E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m308137200 · Cited by 46 · see citing works
Use of 7-Ethoxycoumarin to Monitor Multiple Enzymes in the Human CYP1, CYP2, and CYP3 Families
Waxman, D. J., & Chang, T. K. H. (2006) · Humana Press eBooks · doi:10.1385/1-59259-998-2:153 · Cited by 46 · see citing works
Dick, R. A., Kanne, D. B., & Casida, J. E. (2005) · Chemical Research in Toxicology · doi:10.1021/tx050230x · Cited by 45 · see citing works
Self-citationSwenson, T. L., & Casida, J. E. (2012) · Toxicology Letters · doi:10.1016/j.toxlet.2012.11.027 · Cited by 45 · see citing works
Self-citationMaia, L. B., & Mira, L. (2002) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2002.2781 · Cited by 43 · see citing works
Identification of aldehyde oxidase 1 and aldehyde oxidase homologue 1 as dioxin-inducible genes
Rivera, S. P., Choi, H. H., Chapman, B., Whitekus, M. J., Terao, M., Garattini, E., & Hankinson, O. (2004) · Toxicology · doi:10.1016/j.tox.2004.10.009 · Cited by 41 · see citing works
Advisory committee on pesticides
Challis, T. (1991) · Food and Chemical Toxicology · doi:10.1016/0278-6915(91)90154-y · Cited by 27 · see citing works
Biotransformation of carbazeran in guinea pig: Effect of hydralazine pretreatment
Critchley, D. J. P., Rance, D. J., & Beedham, C. (1994) · Xenobiotica · doi:10.3109/00498259409043219 · Cited by 26 · see citing works
Inter-strain variability in aldehyde oxidase activity in the mouse
Al-Salmy, H. S. (2002) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/s1532-0456(02)00057-1 · Cited by 17 · see citing works
(2007) · Royal Society of Chemistry eBooks · doi:10.1039/9781847551375-00105 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Maia, L. B., & Moura, J. J. G. (2014) · Chemical Reviews · doi:10.1021/cr400518y · Cited by 401 · see citing works
Structure and function of mammalian aldehyde oxidases
Terao, M., Romão, M. J., Leimkühler, S., Bolis, M., Fratelli, M., Coelho, C., Santos-Silva, T., & Garattini, E. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1683-1 · Cited by 112 · see citing works
- Authors
- Swenson, T. L., & Casida, J. E.
- Affiliations
- University of California, Berkeley (US)
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-03-05
- Volume
- 133
- Issue
- 1
- Pages
- 22-28
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2141534876
- Cited by
- 63
- References
- 37
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 10 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 7 · 2013: 5
- FWCI
- 6.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- aldehyde oxidase, imidacloprid, neonicotinoids, nitro group reduction, cytochrome P450, tungsten, hydralazine, Drosophila, insecticide metabolism, liver detoxification, xenobiotic metabolism
- MeSH terms
- Neonicotinoids, Animals, Biotransformation, Cytosol, Drosophila melanogaster, Imidazoles, Insecticides, Liver, Male, Mice, Inbred DBA, Microsomes, Liver, Nitro Compounds, Oxidation-Reduction, Species Specificity, Xenobiotics, Molecular Structure, Aldehyde Oxidase, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
