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Characteristics of membrane transport, metabolism, and target protein binding of cyclic depsipeptide destruxin E in HeLa cells.
Amifuji, Makoto; Inagaki, Mai; Yoshida, Masahito; Doi, Takayuki; Tachikawa, Masanori.
Afiliação
  • Amifuji M; Graduate School of Pharmaceutical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
  • Inagaki M; Graduate School of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
  • Yoshida M; Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8571, Japan.
  • Doi T; Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
  • Tachikawa M; Graduate School of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan. Electronic address: tachik-dds@umin.ac.jp.
Drug Metab Pharmacokinet ; 58: 101028, 2024 Jul 02.
Article em En | MEDLINE | ID: mdl-39265438
ABSTRACT
Cyclic peptides have attracted attention as new modalities for drug development owing to their unique pharmacokinetic and pharmacodynamic properties. Destruxin E, a 19-membered cyclodepsipeptide, is a promising candidate drug for cancer therapy. The purpose of the present study was to clarify the molecular mechanisms underlying membrane transport, metabolism, and the binding for target molecules of destruxin E in human cervical carcinoma HeLa cells used as a model of cancer cells. The influx transport and the intracellular metabolism of destruxin E were non-saturable and saturable, respectively, at up to 10 µM. The intracellular amounts of destruxin E and destruxin E-diol after incubation of destruxin E with the cells significantly decreased at 4 °C compared to those at 37 °C. Destruxin E-diol, but not destruxin E, undergoes efflux transport out of cells via P-gp/MDR1/ABCB1 and BCRP/ABCG2. The epoxide hydrolase EPHX2 functions as a potent metabolizing enzyme that can convert the epoxide of destruxin E to the destruxin E-diol. Treatment with an EPHX2 inhibitor increased the intracellular destruxin E levels and enhanced the inhibitory activity of vacuolar type-H+ ATPase. These results suggest that epoxide hydrolase could be a regulatory factor for intracellular destruxin E levels and its pharmacological activity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Drug Metab Pharmacokinet Assunto da revista: FARMACOLOGIA / METABOLISMO Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Drug Metab Pharmacokinet Assunto da revista: FARMACOLOGIA / METABOLISMO Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão País de publicação: Reino Unido