Characterization of Escherichia coli nitroreductase NfsB in the metabolism of nitrobenzodiazepines

Shiuan Woei LinWu, Cheng Jie Syu, Yu Lian Chen, Andrew H.J. Wang, Fu Chuo Peng

研究成果: 雜誌貢獻文章同行評審

13 引文 斯高帕斯(Scopus)

摘要

Nitrobenzodiazepine (NBDZ) is a sedative-hypnotic drug used in the treatment of anxiety and sleep problems. Overdose of NBDZ may cause severe neurological effects, especially for people in drug abuse or addiction. In the present study, we investigated NBDZ nitroreduction in rat enteric contents and characterized the role of enterobacterial nitroreductase in the reductive pathway. Nitroreduction of flunitrazepam (FZ) was studied in the microsomal membrane fractions of rat liver, jejunum and jejunal microflora using HPLC analysis. In the jejunal microflora, FZ was demonstrated to be significantly reduced to its amino derivative under anaerobic condition. Escherichia coli type I nitroreductase NfsB (EC 1.5.1.34) was found in rat jejunal microflora via PCR technique and Western blotting. The participation of NfsB in FZ nitroreduction was demonstrated from inhibition studies. Kinetic study of the purified recombinant NfsB indicated that nitroreduction of FZ, nitrazepam (NZ) and clonazepam (CZ) are mediated by NfsB, where CZ shows lower kcat/KM ratio than that of the other two. Finally, two other nitroreductases E. cloacae NR (EC 1.6.99.7) and S. typhimurium Cnr were also found to be responsible for FZ nitroreduction. These results provide that the reduction of NBDZ in normal flora is catalyzed by type I nitroreductase NfsB.

原文英語
頁(從 - 到)96-103
頁數8
期刊Biochemical Pharmacology
78
發行號1
DOIs
出版狀態已發佈 - 7月 1 2009
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 藥理

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