ArticleThe Journal of biological chemistry2010
Oxidation of N-Nitrosoalkylamines by human cytochrome P450 2A6: sequential oxidation to aldehydes and carboxylic acids and analysis of reaction steps.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 58 citations in OpenAlex.
- Secukinumab mitigates diethyl nitrosamine-induced acute liver injury in mice via modulating p-ERK/p-eIF2α/CHOP and NLRP3/Caspase-1/IL-1β pathways.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Simplified approaches to kinetic isotope effects in cytochrome P450-catalyzed reactions and relevance to deuterated drugs.Drug metabolism reviews · 2026Review
- Metabolic Activation and DNA Interactions of CarcinogenicInternational journal of molecular sciences · 2022Review
- Digoxin mitigates diethylnitrosamine-induced acute liver injury in mice via limiting production of inflammatory mediators.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2022Article
- Developing Structure-Activity Relationships forComputational toxicology (Amsterdam, Netherlands) · 2021Article
- Review
- Kinetic Modeling of Steady-State Situations in Cytochrome P450 Enzyme Reactions.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Comparative disposition of dimethylaminoethanol and choline in rats and mice following oral or intravenous administration.Toxicology and applied pharmacology · 2019Article
- Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone.The Journal of biological chemistry · 2019Article
- Electron Transfer Control of Reductase versus Monooxygenase: Catalytic C-H Bond Hydroxylation and Alkene Epoxidation by Molecular Oxygen.ACS central science · 2019Article
- Mechanisms of Cytochrome P450-Catalyzed Oxidations.ACS catalysis · 2018Article
- Formation and Cleavage of C-C Bonds by Enzymatic Oxidation-Reduction Reactions.Chemical reviews · 2018Review
- A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s.Journal of visualized experiments : JoVE · 2017Article
- Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions.Methods in enzymology · 2017Article
- Evaluation of Nitrosamide Formation in the Cytochrome P450-Mediated Metabolism of Tobacco-Specific Nitrosamines.Chemical research in toxicology · 2016Article
- Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1: 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL OXYGEN.The Journal of biological chemistry · 2016Article
- Structural and kinetic basis of steroid 17α,20-lyase activity in teleost fish cytochrome P450 17A1 and its absence in cytochrome P450 17A2.The Journal of biological chemistry · 2015Article
- Mechanism of the third oxidative step in the conversion of androgens to estrogens by cytochrome P450 19A1 steroid aromatase.Journal of the American Chemical Society · 2014Article
- Inhibition of human cytochrome P450 2E1 and 2A6 by aldehydes: structure and activity relationships.Chemico-biological interactions · 2014Article
- Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
Cytochrome P450 (P450) 2A6 activates nitrosamines, including N,N-dimethylnitrosamine (DMN) and N,N-diethylnitrosamine (DEN), to alkyl diazohydroxides (which are DNA-alkylating agents) and also aldehydes (HCHO from DMN and CH(3)CHO from DEN). The N-dealkylation of DMN had a high intrinsic kinetic deuterium isotope effect ((D)k(app) approximately 10), which was highly expressed in a variety of competitive and non-competitive experiments. The (D)k(app) for DEN was approximately 3 and not expressed in non-competitive experiments. DMN and DEN were also oxidized to HCO(2)H and CH(3)CO(2)H, respectively. In neither case was a lag observed, which was unexpected considering the k(cat) and K(m) parameters measured for oxidation of DMN and DEN to the aldehydes and for oxidation of the aldehydes to the carboxylic acids. Spectral analysis did not indicate strong affinity of the aldehydes for P450 2A6, but pulse-chase experiments showed only limited exchange with added (unlabeled) aldehydes in the oxidations of DMN and DEN to carboxylic acids. Substoichiometric kinetic bursts were observed in the pre-steady-state oxidations of DMN and DEN to aldehydes. A minimal kinetic model was developed that was consistent with all of the observed phenomena and involves a conformational change of P450 2A6 following substrate binding, equilibrium of the P450-substrate complex with a non-productive form, and oxidation of the aldehydes to carboxylic acids in a process that avoids relaxation of the conformation following the first oxidation (i.e. of DMN or DEN to an aldehyde).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.