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Oxidative monensin metabolism and cytochrome P450 3A content and functions in liver microsomes from horses, pigs, broiler chicks, cattle and rats.
Abstract: The oxidative metabolism of monensin, an ionophore antibiotic extensively used in veterinary practice as a coccidiostat and a growth promoter, was studied in hepatic microsomal preparations from horses, pigs, broiler chicks, cattle and rats. As assayed by the measurement of the amount of the released formaldehyde, the rate of monensin O-demethylation was nearly of the same order of magnitude in all species, but total monensin metabolism, which was estimated by measuring the rate of substrate disappearance by a high-performance liquid chromatography (HPLC) method, was highest in cattle, intermediate in rats, chicks and pigs, and lowest in horses. When expressed as turnover number (nmol of metabolized monensin/min nmol cytochrome P450-1), the catalytic efficiency (chick >> cattle >> pig approximately rat > horse) was found to correlate inversely with the well known interspecies differences in the susceptibility to the toxic effects of the ionophore, which is characterized by an oral LD50 of 2-3 mg/kg bodyweight (bw) in horses, 50-80 mg/kg bw in cattle and 200 mg/kg bw in chicks. Chick and cattle microsomes also displayed both the highest catalytic efficiency toward two P450 3A dependent substrates (erythromycin and triacetyloleandomycin) and the highest immunodetectable levels of proteins cross-reacting with anti rat P450 3A1/2. Further studies are required to define the role played by this isoenzyme in the oxidative biotransformation of the drug in food producing species.
Publication Date: 2002-03-21 PubMed ID: 11903870DOI: 10.1046/j.1365-2885.2001.00362.xGoogle Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The study investigated how the oxidative metabolism of the antibiotic monensin occurs in different animals’ liver preparations, leading to findings of highest metabolism rates in cattle and lowest in horses. The total monensin metabolism rate had an inverse correlation with each species’ known susceptibility to monensin’s toxic effects.
Research Overview
- The research focused on the oxidative metabolism of monensin, a commonly used antibiotic in veterinary medicine. The liver microsomal preparations from horses, pigs, chickens, cattle, and rats were used to study this process.
- Monensin is used as a coccidiostat (prevents coccidiosis, a parasitic disease in animals) and a growth enhancer.
- The methodology involved the measurement of released formaldehyde to gauge the rate of monensin O-demethylation across species.
- Additionally, the overall monensin metabolism was estimated by measuring the rate of substrate disappearance using high-performance liquid chromatography (HPLC).
Main Findings
- The rate of monensin O-demethylation was found to be similar across all monitored species.
- However, the total metabolism of monensin differed among species, with the highest being observed in cattle and the lowest in horses.
- The intermediate rates of monensin metabolism were observed in rats, chicks, and pigs.
- The study found an inverse correlation of the catalytic efficiency (the amount of monensin metabolized per minute per nmol cytochrome P450-1) with the known differences in species susceptibility to monensin’s toxic effects.
Implications and Future Research
- The findings suggest that different species handle the metabolism of monensin differently, which might explain the observed variations in susceptibility to monensin toxicity.
- Notably, the toxicity of monensin is characterized by an oral LD50 of 2-3 mg/kg bodyweight in horses, 50-80 mg/kg in cattle, and 200 mg/kg in chickens.
- High catalytic efficiency in chickens and cattle toward two P450 3A dependent substrates – erythromycin and triacetyloleandomycin – and the presence of high levels of proteins that react with anti-rat P450 3A1/2 was observed.
- More research is necessary to understand the role this particular isoenzyme plays in the oxidative biotransformation of the antibiotic in food-producing species.
Cite This Article
APA
Nebbia C, Ceppa L, Dacasto M, Nachtmann C, Carletti M.
(2002).
Oxidative monensin metabolism and cytochrome P450 3A content and functions in liver microsomes from horses, pigs, broiler chicks, cattle and rats.
J Vet Pharmacol Ther, 24(6), 399-403.
https://doi.org/10.1046/j.1365-2885.2001.00362.x Publication
Researcher Affiliations
- Dipartimento di Patologia Animale, Sezione di Farmacologia e Tossicologia, Università di Torino, Via Leonardo da Vinci 41, Grugliasco, Italia. cnebbia@veter.unito.it
MeSH Terms
- Animal Population Groups / metabolism
- Animals
- Antiprotozoal Agents / pharmacokinetics
- Antiprotozoal Agents / pharmacology
- Aryl Hydrocarbon Hydroxylases
- Biotransformation
- Blotting, Western / veterinary
- Cats / metabolism
- Cattle / metabolism
- Chickens / metabolism
- Chromatography, High Pressure Liquid / veterinary
- Cytochrome P-450 CYP3A
- Cytochrome P-450 Enzyme System / drug effects
- Cytochrome P-450 Enzyme System / metabolism
- Electrophoresis, Polyacrylamide Gel / veterinary
- Horses / metabolism
- Ionophores / pharmacokinetics
- Ionophores / pharmacology
- Male
- Microsomes, Liver / drug effects
- Microsomes, Liver / metabolism
- Monensin / pharmacokinetics
- Monensin / pharmacology
- Oxidation-Reduction
- Oxidoreductases, N-Demethylating / drug effects
- Oxidoreductases, N-Demethylating / metabolism
- Rats / metabolism
- Swine / metabolism
Citations
This article has been cited 15 times.- Ekinci İB, Chłodowska A, Olejnik M. Ionophore Toxicity in Animals: A Review of Clinical and Molecular Aspects. Int J Mol Sci 2023 Jan 15;24(2).
- Kandeel M, Al-Taher A, Venugopala KN, Marzok M, Morsy M, Nagaraja S. Camel Proteins and Enzymes: A Growing Resource for Functional Evolution and Environmental Adaptation. Front Vet Sci 2022;9:911511.
- Cantiello M, Carletti M, Giantin M, Gardini G, Capolongo F, Cascio P, Pauletto M, Girolami F, Dacasto M, Nebbia C. Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization. Int J Mol Sci 2022 Mar 24;23(7).
- Gray P, Jenner R, Norris J, Page S, Browning G. Antimicrobial prescribing guidelines for poultry. Aust Vet J 2021 Jun;99(6):181-235.
- Smith JS, Varga A, Schober KE. Comparison of Two Commercially Available Immunoassays for the Measurement of Bovine Cardiac Troponin I in Cattle With Induced Myocardial Injury. Front Vet Sci 2020;7:531.
- Radko L, Olejnik M, Posyniak A. Primary Human Hepatocytes, but Not HepG2 or Balb/c 3T3 Cells, Efficiently Metabolize Salinomycin and Are Resistant to Its Cytotoxicity. Molecules 2020 Mar 5;25(5).
- Giantin M, Rahnasto-Rilla M, Tolosi R, Lucatello L, Pauletto M, Guerra G, Pezzato F, Lopparelli RM, Merlanti R, Carnier P, Capolongo F, Honkakoski P, Dacasto M. Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle. Sci Rep 2019 Dec 23;9(1):19672.
- Kotthoff L, Lisec J, Schwerdtle T, Koch M. Prediction of Transformation Products of Monensin by Electrochemistry Compared to Microsomal Assay and Hydrolysis. Molecules 2019 Jul 27;24(15).
- Giantin M, Küblbeck J, Zancanella V, Prantner V, Sansonetti F, Schoeniger A, Tolosi R, Guerra G, Da Ros S, Dacasto M, Honkakoski P. DNA elements for constitutive androstane receptor- and pregnane X receptor-mediated regulation of bovine CYP3A28 gene. PLoS One 2019;14(3):e0214338.
- Gonzalez M, Barkema HW, Keefe GP. Monensin toxicosis in a dairy herd. Can Vet J 2005 Oct;46(10):910-2.
- Craigmill AL, Cortright KA. Interspecies considerations in the evaluation of human food safety for veterinary drugs. AAPS PharmSci 2002;4(4):E34.
- Ichinose P, Munafó JP, Miró MV, Valente M, Moreno-Torrejón L, Larsen K, Lanusse C, Lifschitz A, Virkel G. Effects of Newer Veterinary Macrolide Antimicrobials on the CYP3A-Dependent Metabolism in Cattle Liver Microsomes: Potential Metabolic Drug-Drug Interaction with Monensin. Animals (Basel) 2026 Jan 25;16(3).
- Montanucci L, Iori S, Lahtela-Kakkonen M, Pauletto M, Giantin M, Dacasto M. Impact of Missense Mutations on AFB1 Metabolism in Bovine Cytochrome P4503A Isoforms: A Computational Mutagenesis and Molecular Docking Analysis. Int J Mol Sci 2024 Nov 22;25(23).
- Sun P, Lootens O, Kabeta T, Reckelbus D, Furman N, Cao X, Zhang S, Antonissen G, Croubels S, De Boevre M, De Saeger S. Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens. Toxins (Basel) 2024 Mar 20;16(3).
- Svoboda M, Huml O, Chomat P, Honzlova A, Illek J, Svobodova Z, Hofmannova L, Modra H. Accidental salinomycin intoxication in European fallow deer (Dama dama L.). Vet Med (Praha) 2024 Jan;69(1):18-29.
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