ArticleThe Journal of biological chemistry2008
CYP2E1 substrate inhibition. Mechanistic interpretation through an effector site for monocyclic compounds.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
32 citing papers in PubMed, 73 citations in OpenAlex.
- Opposing Roles of CYP2E1 and ALDH2 in Binge Alcohol-Mediated Cerebellar Damage.International journal of molecular sciences · 2026Article
- Acute Acetaminophen Hepatotoxicity And Platelet Dysfunction.Journal of medical toxicology : official journal of the American College of Medical Toxicology · 2025Article
- Linking Benzene, in Utero Carcinogenicity and Fetal Hematopoietic Stem Cell Niches: A Mechanistic Review.International journal of molecular sciences · 2023Review
- Treatment with omega-3 PUFAs does not increase the risk of CYP2E1-dependent oxidative stress and diabetic liver pathology.Frontiers in endocrinology · 2022Article
- Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 1. Theoretical Considerations.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Validation of an HPLC Method for the Simultaneous Quantification of Metabolic Reaction Products Catalysed by CYP2E1 Enzyme Activity: Inhibitory Effect of Cytochrome P450 Enzyme CYP2E1 by Salicylic Acid in Rat Liver Microsomes.Molecules (Basel, Switzerland) · 2020Article
- Delayed Treatment With 4-Methylpyrazole Protects Against Acetaminophen Hepatotoxicity in Mice by Inhibition of c-Jun n-Terminal Kinase.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Correction to "Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213".Biochemistry · 2019Article
- Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213.Biochemistry · 2019Article
- Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4.Biochemistry · 2018Article
- Spectroscopic studies of the cytochrome P450 reaction mechanisms.Biochimica et biophysica acta. Proteins and proteomics · 2018Review
- Kinetic characterizations of diallyl sulfide analogs for their novel role as CYP2E1 enzyme inhibitors.Pharmacology research & perspectives · 2017Article
- Zebrafish have an ethanol-inducible hepatic 4-nitrophenol hydroxylase that is not CYP2E1-like.Environmental toxicology and pharmacology · 2017Article
- Toxicological Implications of Mitochondrial Localization of CYP2E1.Toxicology research · 2017Article
- Functioning of drug-metabolizing microsomal cytochrome P450s: In silico probing of proteins suggests that the distal heme 'active site' pocket plays a relatively 'passive role' in some enzyme-substrate interactions.In silico pharmacology · 2016Article
- Effect of BI-1 on insulin resistance through regulation of CYP2E1.Scientific reports · 2016Article
- Subcellular localization of rat CYP2E1 impacts metabolic efficiency toward common substrates.Toxicology · 2015Article
- Cooperativity in CYP2E1 metabolism of acetaminophen and styrene mixtures.Biochemical pharmacology · 2015Article
- Structural basis for cooperative binding of azoles to CYP2E1 as interpreted through guided molecular dynamics simulations.Journal of molecular graphics & modelling · 2015Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
In this study we offer a mechanistic interpretation of the previously known but unexplained substrate inhibition observed for CYP2E1. At low substrate concentrations, p-nitrophenol (pNP) was rapidly turned over (47 min(-1)) with relatively low K(m) (24 microM); nevertheless, at concentrations of >100 microM, the rate of pNP oxidation gradually decreased as a second molecule bound to CYP2E1 through an effector site (K(ss) = 260 microm), which inhibited activity at the catalytic site. 4-Methylpyrazole (4MP) was a potent inhibitor for both sites through a mixed inhibition mechanism. The K(i) for the catalytic site was 2.0 microM. Although we were unable to discriminate whether an EIS or ESI complex formed, the respective inhibition constants were far lower than K(ss). Bicyclic indazole (IND) inhibited catalysis through a single CYP2E1 site (K(i) = 0.12 microM). Similarly, 4MP and IND yielded type II binding spectra that reflected the association of either two 4MP or one IND molecule(s) to CYP2E1, respectively. Based on computational docking studies with a homology model for CYP2E1, the two sites for monocyclic molecules, pNP and 4MP, exist within a narrow channel connecting the active site to the surface of the enzyme. Because of the presence of the heme iron, one site supports catalysis, whereas the other more distal effector site binds molecules that can influence the binding orientation and egress of molecules for the catalytic site. Although IND did not bind these sites simultaneously, the presence of IND at the catalytic site blocked binding at the effector site.
Indexed as
Identifiers
What OpenQuestion holds
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.