Inter-species differences between humans and other mammals in the in vitro metabolism of carbofuran and the role of human CYP enzymes
Abass, Khaled; Reponen, Petri; Anyanwu, Brilliance; Pelkonen, Olavi (2023-08-11)
Elsevier
11.08.2023
Abass, K., Reponen, P., Anyanwu, B., & Pelkonen, O. (2023). Inter-species differences between humans and other mammals in the in vitro metabolism of carbofuran and the role of human CYP enzymes. In Environmental Toxicology and Pharmacology (Vol. 102, p. 104243). Elsevier BV. https://doi.org/10.1016/j.etap.2023.104243.
https://creativecommons.org/licenses/by/4.0/
© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://creativecommons.org/licenses/by/4.0/
© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://creativecommons.org/licenses/by/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202311293426
https://urn.fi/URN:NBN:fi:oulu-202311293426
Tiivistelmä
Abstract
This study investigated the metabolic transformation of carbofuran in seven species of mammals using LC-MS/MS and liver microsomes. The results revealed species-specific differences in metabolite formation, indicating the potential role of metabolic pathways in toxicity and risk assessment. The majority of carbofuran was metabolized through the 3-hydroxycarbofuran pathway, with the highest levels observed in dogLM and the lowest in humanLM. Further analysis was conducted to investigate the human cytochrome P450-mediated metabolism of carbofuran, with CYP3A4 being found to be the most efficient enzyme with the highest contribution to the 3-hydroxycarbofuran pathway. Inhibition of CYP3A4 with ketoconazole resulted in a substantial decrease in carbofuran metabolism. In addition, carbofuran exhibited inhibitory effects on human CYP3A4 and CYP2B6, demonstrating the potential for carbofuran to interact with these enzymes. The findings highlight the importance of in vitro screening for metabolic processes and provide insights into the biotransformation of carbofuran.
This study investigated the metabolic transformation of carbofuran in seven species of mammals using LC-MS/MS and liver microsomes. The results revealed species-specific differences in metabolite formation, indicating the potential role of metabolic pathways in toxicity and risk assessment. The majority of carbofuran was metabolized through the 3-hydroxycarbofuran pathway, with the highest levels observed in dogLM and the lowest in humanLM. Further analysis was conducted to investigate the human cytochrome P450-mediated metabolism of carbofuran, with CYP3A4 being found to be the most efficient enzyme with the highest contribution to the 3-hydroxycarbofuran pathway. Inhibition of CYP3A4 with ketoconazole resulted in a substantial decrease in carbofuran metabolism. In addition, carbofuran exhibited inhibitory effects on human CYP3A4 and CYP2B6, demonstrating the potential for carbofuran to interact with these enzymes. The findings highlight the importance of in vitro screening for metabolic processes and provide insights into the biotransformation of carbofuran.
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