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Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes

Chronic intraperitoneal injection of thioacetamide (TAA) in rats has been used as an animal model of human cirrhosis to study the effects of the disease on drug metabolism. However, TAA inhibits P450 enzymes directly and independently of cirrhosis. We investigated the effects of chronic cirrhosis in...

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Autores principales: Chandrashekar, Devaraj Venkatapura, DuBois, Barent N., Rashid, Mamunur, Mehvar, Reza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10100077/
https://www.ncbi.nlm.nih.gov/pubmed/36370118
http://dx.doi.org/10.1111/bcpt.13813
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author Chandrashekar, Devaraj Venkatapura
DuBois, Barent N.
Rashid, Mamunur
Mehvar, Reza
author_facet Chandrashekar, Devaraj Venkatapura
DuBois, Barent N.
Rashid, Mamunur
Mehvar, Reza
author_sort Chandrashekar, Devaraj Venkatapura
collection PubMed
description Chronic intraperitoneal injection of thioacetamide (TAA) in rats has been used as an animal model of human cirrhosis to study the effects of the disease on drug metabolism. However, TAA inhibits P450 enzymes directly and independently of cirrhosis. We investigated the effects of chronic cirrhosis in rats, induced by 10 weeks of intraperitoneal TAA, on the P450 enzymes after a 10‐day washout period to eliminate TAA. Liver histology and serum biomarkers of hepatic function confirmed cirrhosis in all animals. Microsomal total P450 content, P450 reductase activity and ethoxycoumarin O‐deethylase activity, a general marker of P450 activity, were significantly reduced by 30%–50% in cirrhotic animals. Additionally, the protein content and Michaelis–Menten kinetics of the activities of CYP2D, CYP2E1 and CYP3A were investigated. Whereas cirrhosis reduced the microsomal protein contents of CYP2D and CYP3A by 70% and 30%, respectively, the protein contents of CYP2E1 were not affected. However, the activities of all the tested isoenzymes were substantially lower in the cirrhotic livers. It is concluded that the TAA model of cirrhosis that incorporates a 10‐day washout period after intraperitoneal injection of the chemical to rats produces isoenzyme‐selective reductions in the P450 proteins or activities, which are independent of the direct inhibitory effects of TAA.
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spelling pubmed-101000772023-04-14 Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes Chandrashekar, Devaraj Venkatapura DuBois, Barent N. Rashid, Mamunur Mehvar, Reza Basic Clin Pharmacol Toxicol Original Articles Chronic intraperitoneal injection of thioacetamide (TAA) in rats has been used as an animal model of human cirrhosis to study the effects of the disease on drug metabolism. However, TAA inhibits P450 enzymes directly and independently of cirrhosis. We investigated the effects of chronic cirrhosis in rats, induced by 10 weeks of intraperitoneal TAA, on the P450 enzymes after a 10‐day washout period to eliminate TAA. Liver histology and serum biomarkers of hepatic function confirmed cirrhosis in all animals. Microsomal total P450 content, P450 reductase activity and ethoxycoumarin O‐deethylase activity, a general marker of P450 activity, were significantly reduced by 30%–50% in cirrhotic animals. Additionally, the protein content and Michaelis–Menten kinetics of the activities of CYP2D, CYP2E1 and CYP3A were investigated. Whereas cirrhosis reduced the microsomal protein contents of CYP2D and CYP3A by 70% and 30%, respectively, the protein contents of CYP2E1 were not affected. However, the activities of all the tested isoenzymes were substantially lower in the cirrhotic livers. It is concluded that the TAA model of cirrhosis that incorporates a 10‐day washout period after intraperitoneal injection of the chemical to rats produces isoenzyme‐selective reductions in the P450 proteins or activities, which are independent of the direct inhibitory effects of TAA. John Wiley and Sons Inc. 2022-11-24 2023-02 /pmc/articles/PMC10100077/ /pubmed/36370118 http://dx.doi.org/10.1111/bcpt.13813 Text en © 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Chandrashekar, Devaraj Venkatapura
DuBois, Barent N.
Rashid, Mamunur
Mehvar, Reza
Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes
title Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes
title_full Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes
title_fullStr Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes
title_full_unstemmed Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes
title_short Effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and Michaelis–Menten kinetics of cytochrome P450 enzymes in the rat liver microsomes
title_sort effects of chronic cirrhosis induced by intraperitoneal thioacetamide injection on the protein content and michaelis–menten kinetics of cytochrome p450 enzymes in the rat liver microsomes
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10100077/
https://www.ncbi.nlm.nih.gov/pubmed/36370118
http://dx.doi.org/10.1111/bcpt.13813
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