Identification of Ketene-Reactive Intermediate of Erlotinib Possibly Responsible for Inactivation of P450 Enzymes.

Zhao, H ; Li, S ; et al.

In: Drug metabolism and disposition: the biological fate of chemicals, Jg. 46 (2018-04-01), Heft 4, S. 442-450

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Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of nonsmall cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of cytochrome P450(CYPs) 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent. CYPs 3A4 and 3A5 mainly contributed to the bioactivation of ELT. Microsomal incubation study showed that the ketene intermediate covalently modified the enzyme protein at lysine residues and destroyed the structure of heme. The vinyl and ethyl analogs of ELT showed minor enzyme inhibitory effect (less than 20%), whereas ELT inactivated more than 60% of the enzyme. The present study provided a novel bioactivation pathway of ELT and facilitated the understanding of the mechanisms of ELT-induced mechanism-based enzyme inactivation and liver injury.

Titel:	Identification of Ketene-Reactive Intermediate of Erlotinib Possibly Responsible for Inactivation of P450 Enzymes.
Autor/in / Beteiligte Person:	Zhao, H ; Li, S ; Yang, Z ; Peng, Y ; Chen, X ; Zheng, J
Link:	Full Text Finder (Volltext)
Zeitschrift:	Drug metabolism and disposition: the biological fate of chemicals, Jg. 46 (2018-04-01), Heft 4, S. 442-450
Veröffentlichung:	[Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.], 2018
Medientyp:	academicJournal
ISSN:	1521-009X (electronic)
DOI:	10.1124/dmd.117.079327
Schlagwort:	Chemical and Drug Induced Liver Injury metabolism Heme metabolism Humans Microsomes, Liver metabolism Protein Binding physiology Cytochrome P-450 CYP3A metabolism Cytochrome P-450 Enzyme Inhibitors metabolism Erlotinib Hydrochloride metabolism Ethylenes metabolism Ketones metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Drug Metab Dispos] 2018 Apr; Vol. 46 (4), pp. 442-450. <i>Date of Electronic Publication: </i>2018 Jan 19. MeSH Terms: Cytochrome P-450 CYP3A / metabolism ; Cytochrome P-450 Enzyme Inhibitors / metabolism ; Erlotinib Hydrochloride / metabolism ; Ethylenes / metabolism ; Ketones / *metabolism ; Chemical and Drug Induced Liver Injury / metabolism ; Heme / metabolism ; Humans ; Microsomes, Liver / metabolism ; Protein Binding / physiology Substance Nomenclature: 0 (Cytochrome P-450 Enzyme Inhibitors) ; 0 (Ethylenes) ; 0 (Ketones) ; 42VZT0U6YR (Heme) ; DA87705X9K (Erlotinib Hydrochloride) ; EC 1.14.14.1 (Cytochrome P-450 CYP3A) ; LEP3SM032A (ketene) Entry Date(s): Date Created: 20180121 Date Completed: 20181105 Latest Revision: 20181105 Update Code: 20231215

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