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Drug Metab Pharmacokinet

Title:		Development of fluorescent-labeled trapping reagents based on cysteine to detect soft and hard electrophilic reactive metabolites
Author(s):		Shibazaki C; Ohe T; Takahashi K; Nakamura S; Mashino T;
Address:		"Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: ohe-tm@pha.keio.ac.jp. Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo, Japan. Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: mashino-td@keio.jp"
Journal Title:		Drug Metab Pharmacokinet
Year:		2021
Volume:		20210415
Issue:
Page Number:		100386 -
DOI:		10.1016/j.dmpk.2021.100386
ISSN/ISBN:		1880-0920 (Electronic) 1347-4367 (Linking)
Abstract:		"Trapping assays are conducted at lead optimization stages to detect reactive metabolites (RMs) that can contribute to drug toxicity. The commonly used dansyl glutathione (dGSH) provides a sensitive analysis owing to the fluorescent label, however, it captures only soft electrophilic RMs. TRs for hard electrophilic RMs, few of which are labeled fluorescently, can detect hard electrophilic aldehydes only by forming unstable imine derivatives. In this study, we aimed to develop novel fluorescently labeled TRs that detect both soft and hard electrophilic RMs and form stable ring structures with aldehydes. We designed four dansylated TRs based on cysteine, which has both soft and hard nucleophilic groups. To evaluate the reactivity of the TRs, we incubated them with several substrates and found that one of the TRs (CysGlu-Dan) detected all the soft and hard electrophilic RMs. We also examined the inhibition potential of each TR for seven major CYPs involved in drug metabolism and found that CysGlu-Dan showed an inhibitory profile similar to that of dGSH. In conclusion, CysGlu-Dan can be used to evaluate the risk of RMs in drug discovery"
Keywords:		"Antioxidant Response Elements Biomarkers, Pharmacological/analysis Chromatography/methods *Cysteine/chemistry/metabolism Cytochrome P-450 Enzyme System/metabolism *Drug-Related Side Effects and Adverse Reactions/diagnosis/metabolism/prevention & control H;"
Notes:		"MedlineShibazaki, Chikako Ohe, Tomoyuki Takahashi, Kyoko Nakamura, Shigeo Mashino, Tadahiko eng England 2021/06/07 Drug Metab Pharmacokinet. 2021 Aug; 39:100386. doi: 10.1016/j.dmpk.2021.100386. Epub 2021 Apr 15"