Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo
Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxic...
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| Veröffentlicht in: | Chemical research in toxicology 2024-06, Vol.37 (6), p.935-943 |
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| container_title | Chemical research in toxicology |
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| creator | Li, Ximei Xin, Lihua Yang, Lan Yang, Yi Li, Wei Zhang, Mingyu Liao, Yufen Sun, Chen Li, Weiwei Peng, Ying Zheng, Jiang |
| description | Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL. |
| doi_str_mv | 10.1021/acs.chemrestox.4c00008 |
| format | Article |
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The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.</description><identifier>ISSN: 0893-228X</identifier><identifier>EISSN: 1520-5010</identifier><identifier>DOI: 10.1021/acs.chemrestox.4c00008</identifier><identifier>PMID: 38761382</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amitriptyline - metabolism ; Animals ; Cells, Cultured ; Cytochrome P-450 CYP3A - metabolism ; Epoxy Compounds - chemistry ; Epoxy Compounds - metabolism ; Epoxy Compounds - toxicity ; Glutathione - metabolism ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Male ; Microsomes, Liver - metabolism ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Chemical research in toxicology, 2024-06, Vol.37 (6), p.935-943</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a301t-30117a94b53c8f763950cc8f09af10251ee8745deaf2fa65143f8d6e29437a5d3</cites><orcidid>0000-0001-7921-3727 ; 0000-0002-8187-2147</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00008$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.chemrestox.4c00008$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,778,782,2754,27059,27907,27908,56721,56771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38761382$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Ximei</creatorcontrib><creatorcontrib>Xin, Lihua</creatorcontrib><creatorcontrib>Yang, Lan</creatorcontrib><creatorcontrib>Yang, Yi</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Zhang, Mingyu</creatorcontrib><creatorcontrib>Liao, Yufen</creatorcontrib><creatorcontrib>Sun, Chen</creatorcontrib><creatorcontrib>Li, Weiwei</creatorcontrib><creatorcontrib>Peng, Ying</creatorcontrib><creatorcontrib>Zheng, Jiang</creatorcontrib><title>Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo</title><title>Chemical research in toxicology</title><addtitle>Chem. Res. Toxicol</addtitle><description>Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.</description><subject>Amitriptyline - metabolism</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Epoxy Compounds - chemistry</subject><subject>Epoxy Compounds - metabolism</subject><subject>Epoxy Compounds - toxicity</subject><subject>Glutathione - metabolism</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Male</subject><subject>Microsomes, Liver - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0893-228X</issn><issn>1520-5010</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE9PwyAYxonRuDn9CkuPXjr5Uyg9LsvUJVu8qPFGGIXI0pYKzLhvL0unHuXwwhue5-HlB8AUwRmCGN1JFWbqXbdeh-i-ZoWCafEzMEYUw5xCBM_BGPKK5BjztxG4CmEHIUre8hKMCC8ZIhyPwWZV6y5aY5WM1nWZM5nssmXvvmyts42OcusaG_XxYt7a6G0fD43tdLbqstfUu6Svh-bTXYMLI5ugb077BLzcL58Xj_n66WG1mK9zSSCKeSqolFWxpURxUzJSUajSCVbSpAkp0pqXBa21NNhIRlFBDK-ZxlVBSklrMgG3Q27v3cc-IRCtDUo3jey02wdBIGWMYU5xkrJBqrwLwWsjem9b6Q8CQXFEKRJK8YdSnFAm4_T0xn7b6vrX9sMuCfAgOAbs3N536cv_pX4DpieEhA</recordid><startdate>20240617</startdate><enddate>20240617</enddate><creator>Li, Ximei</creator><creator>Xin, Lihua</creator><creator>Yang, Lan</creator><creator>Yang, Yi</creator><creator>Li, Wei</creator><creator>Zhang, Mingyu</creator><creator>Liao, Yufen</creator><creator>Sun, Chen</creator><creator>Li, Weiwei</creator><creator>Peng, Ying</creator><creator>Zheng, Jiang</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7921-3727</orcidid><orcidid>https://orcid.org/0000-0002-8187-2147</orcidid></search><sort><creationdate>20240617</creationdate><title>Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo</title><author>Li, Ximei ; Xin, Lihua ; Yang, Lan ; Yang, Yi ; Li, Wei ; Zhang, Mingyu ; Liao, Yufen ; Sun, Chen ; Li, Weiwei ; Peng, Ying ; Zheng, Jiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a301t-30117a94b53c8f763950cc8f09af10251ee8745deaf2fa65143f8d6e29437a5d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Amitriptyline - metabolism</topic><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Epoxy Compounds - chemistry</topic><topic>Epoxy Compounds - metabolism</topic><topic>Epoxy Compounds - toxicity</topic><topic>Glutathione - metabolism</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>Male</topic><topic>Microsomes, Liver - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Ximei</creatorcontrib><creatorcontrib>Xin, Lihua</creatorcontrib><creatorcontrib>Yang, Lan</creatorcontrib><creatorcontrib>Yang, Yi</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Zhang, Mingyu</creatorcontrib><creatorcontrib>Liao, Yufen</creatorcontrib><creatorcontrib>Sun, Chen</creatorcontrib><creatorcontrib>Li, Weiwei</creatorcontrib><creatorcontrib>Peng, Ying</creatorcontrib><creatorcontrib>Zheng, Jiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical research in toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Ximei</au><au>Xin, Lihua</au><au>Yang, Lan</au><au>Yang, Yi</au><au>Li, Wei</au><au>Zhang, Mingyu</au><au>Liao, Yufen</au><au>Sun, Chen</au><au>Li, Weiwei</au><au>Peng, Ying</au><au>Zheng, Jiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo</atitle><jtitle>Chemical research in toxicology</jtitle><addtitle>Chem. Res. Toxicol</addtitle><date>2024-06-17</date><risdate>2024</risdate><volume>37</volume><issue>6</issue><spage>935</spage><epage>943</epage><pages>935-943</pages><issn>0893-228X</issn><eissn>1520-5010</eissn><abstract>Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38761382</pmid><doi>10.1021/acs.chemrestox.4c00008</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-7921-3727</orcidid><orcidid>https://orcid.org/0000-0002-8187-2147</orcidid></addata></record> |
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| subjects | Amitriptyline - metabolism Animals Cells, Cultured Cytochrome P-450 CYP3A - metabolism Epoxy Compounds - chemistry Epoxy Compounds - metabolism Epoxy Compounds - toxicity Glutathione - metabolism Hepatocytes - drug effects Hepatocytes - metabolism Male Microsomes, Liver - metabolism Rats Rats, Sprague-Dawley |
| title | Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo |
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