Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes
Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were differ...
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1093696/full |
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| author | Yingzi Li Xiaoyan Liu Ludi Li Tao Zhang Yadong Gao Kewu Zeng Qi Wang Qi Wang Qi Wang |
| author_facet | Yingzi Li Xiaoyan Liu Ludi Li Tao Zhang Yadong Gao Kewu Zeng Qi Wang Qi Wang Qi Wang |
| author_sort | Yingzi Li |
| collection | DOAJ |
| description | Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role. |
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| id | doaj.art-9f88e3e8b20b445fb77e98721e12de32 |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T20:33:05Z |
| publishDate | 2023-01-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-9f88e3e8b20b445fb77e98721e12de322023-01-25T05:26:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-01-011410.3389/fphar.2023.10936961093696Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomesYingzi Li0Xiaoyan Liu1Ludi Li2Tao Zhang3Yadong Gao4Kewu Zeng5Qi Wang6Qi Wang7Qi Wang8Department of Toxicology, School of Public Health, Peking University, Beijing, ChinaDepartment of Toxicology, School of Public Health, Peking University, Beijing, ChinaDepartment of Toxicology, School of Public Health, Peking University, Beijing, ChinaDepartment of Toxicology, School of Public Health, Peking University, Beijing, ChinaDepartment of Toxicology, School of Public Health, Peking University, Beijing, ChinaState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, ChinaDepartment of Toxicology, School of Public Health, Peking University, Beijing, ChinaKey Laboratory of State Administration of Traditional Chinese Medicine for Compatibility Toxicology, Beijing, ChinaKey Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, ChinaEupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role.https://www.frontiersin.org/articles/10.3389/fphar.2023.1093696/fulleupalinolide Aeupalinolide Bhuman liver microsomescarboxylesterasecytochrome P450metabolic stability |
| spellingShingle | Yingzi Li Xiaoyan Liu Ludi Li Tao Zhang Yadong Gao Kewu Zeng Qi Wang Qi Wang Qi Wang Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes Frontiers in Pharmacology eupalinolide A eupalinolide B human liver microsomes carboxylesterase cytochrome P450 metabolic stability |
| title | Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes |
| title_full | Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes |
| title_fullStr | Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes |
| title_full_unstemmed | Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes |
| title_short | Characterization of the metabolism of eupalinolide A and B by carboxylesterase and cytochrome P450 in human liver microsomes |
| title_sort | characterization of the metabolism of eupalinolide a and b by carboxylesterase and cytochrome p450 in human liver microsomes |
| topic | eupalinolide A eupalinolide B human liver microsomes carboxylesterase cytochrome P450 metabolic stability |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1093696/full |
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