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发表时间：2022-10-10

发表刊物：药学学报

卷号：52

期号：1

页面范围：58-65

ISSN号：0513-4870

摘要：Carboxylesterase 1 (CE1)is an important serine hydrolase in mammals,
   which involved in the hydrolysis of a variety of compounds (endogenous
   substrates like cholesterol and xenobiotic compounds like ester-contain
   drugs and pesticides). This study aimed to design and develop the
   fluorescent probe substrates for human carboxylesterase 1 (hCE1), on the
   basis of the structural features of hCE1 preferred substrates. Four
   carboxylic esters deriving from BODIPY-8-carboxylic acid were designed
   and synthesized. After then, reaction phenotyping assays and chemical
   inhibition assays were used to evaluate the selectivity of these four
   ester derivatives towards hCE1. Our results clearly demonstrated that
   the substrate specificity of these ester substrates towards hCE1 would
   be improved with the decrease of the alcohol group on
   BODIPY-8-carboxylesters, while BODIPY-8-carboxylesters with small
   alcohol groups including methyl (BCM)and ethyl (BCE)esters could serve
   as the ideal probe substrates for hCE1. Given that BCM exhibit rapid
   hydrolytic rate in hCE1, we further investigate the enzymatic kinetics
   of this fluorescent probe substrate in both human liver microsomes
   (HLM)and recombinant hCE1, as well as to explore its potential
   application in high-throughput screening of hCE1 inhibitors by using HLM
   as enzyme source. The results showed that the kinetic behaviors and the
   affinity of BCM in HLM is much closed to those in recombinant hCE1,
   implying that hCE1 played the key roles in BCM hydrolysis in HLM.
   Furthermore, the inhibition study demonstrated that BCM could be used
   for rapid screening and characterization of hCE1 inhibitors, by using
   HLM to replace recombinant hCE1 as enzyme source.

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