Related Experiment Video

Updated: Aug 24, 2026

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
10:01

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

Published on: June 23, 2026

Inhibition of carcinogen-bioactivating cytochrome P450 1 isoforms by amiloride derivatives

Lydie Sparfel1, Laurence Huc, Marc Le Vee

  • 1INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 2 avenue du Prof Léon Bernard, 35043 Rennes cédex, France. lydie.sparfel@rennes.inserm.fr

Biochemical Pharmacology
|April 15, 2004
PubMed

Insights

Amiloride derivatives like EIPA potently inhibit cytochrome P450 (CYP) 1 enzymes, reducing the metabolism of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and their toxic effects. This suggests EIPA

Area of Science:

  • Biochemistry
  • Toxicology
  • Pharmacology

Background:

  • Cytochrome P450 (CYP) 1 enzymes metabolize carcinogenic polycyclic aromatic hydrocarbons (PAHs) into mutagenic compounds.
  • PAH interaction with the arylhydrocarbon receptor induces cellular expression of CYP1 enzymes.
  • Benzo(a)pyrene (BP) is a carcinogenic PAH metabolized by CYP1 isoforms.

Purpose of the Study:

  • To investigate the effects of amiloride derivatives, specifically 5-(N-ethyl-N-isopropyl)amiloride (EIPA), on CYP1 enzyme activity.
  • To determine if EIPA affects PAH-mediated induction of CYP1 enzymes.
  • To assess the impact of EIPA on BP metabolism and associated cellular toxicity.

Main Methods:

  • Assessed EIPA's effect on CYP1-related ethoxyresorufine O-deethylase (EROD) activity in liver cells and microsomes.
  • Utilized human recombinant CYP1A1, CYP1A2, and CYP1B1 enzymes to study EIPA's inhibitory mechanism.
  • Measured BP metabolism, BP-derived DNA adducts, and BP-induced apoptosis in liver cells treated with EIPA.

Main Results:

  • EIPA demonstrated potent, dose-dependent inhibition of CYP1-related EROD activity.
  • EIPA competitively inhibited human recombinant CYP1A1, CYP1A2, and CYP1B1 enzyme activities.
  • EIPA reduced BP metabolism, decreased BP-DNA adduct formation, and diminished BP-induced apoptosis without affecting CYP1A1 induction.

Conclusions:

  • Amiloride derivatives, such as EIPA, effectively inhibit CYP1 enzyme activity.
  • EIPA's inhibition of CYP1 enzymes leads to decreased metabolism of PAHs and reduced associated toxicity.
  • EIPA shows potential as a preventative agent against chemical carcinogen toxicity, particularly PAHs.

More Related Videos

Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling09:33

Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling

Published on: March 20, 2018

Related Concept Videos

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
Mutagenicity and Carcinogenicity01:25

Mutagenicity and Carcinogenicity

Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Pharmacokinetics: Drug–Drug Interactions01:25

Pharmacokinetics: Drug–Drug Interactions

Drug interactions occur when the pharmacological effect of one drug is altered by another substance, either enhancing or diminishing its activity. The drug whose activity is altered is known as the object drug, and the substance causing the alteration is called the agent drug or the precipitant. The net effects of these interactions are mostly undesirable, leading to decreased effectiveness or increased adverse effects. In rare cases, interactions can be beneficial, such as the enhanced...
Antihypertensive Drugs: Potassium-Sparing Diuretics01:28

Antihypertensive Drugs: Potassium-Sparing Diuretics

Liddle syndrome is a genetically inherited form of hypertension characterized by the overactivity of epithelial sodium channels in the nephron, the functional unit of the kidney. This heightened activity leads to increased sodium reabsorption and excessive excretion of potassium. To counteract this, potassium-sparing diuretics such as amiloride are used. They function by blocking these sodium channels, thereby reducing the influx of sodium into the epithelial cells and minimizing the loss of...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...