A1 Refereed original research article in a scientific journal
Substrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes: In Vitro Enzyme Kinetics and In Silico Modeling
Authors: Juvonen Risto O, Ahinko Mira, Jokinen Elmeri M., Huuskonen Juhani, Raunio Hannu, Pentikäinen Olli T
Publisher: AMER CHEMICAL SOC
Publication year: 2021
Journal: ACS Omega
Journal name in source: ACS OMEGA
Journal acronym: ACS OMEGA
Volume: 6
Issue: 17
First page : 11286
Last page: 11296
Number of pages: 11
ISSN: 2470-1343
DOI: https://doi.org/10.1021/acsomega.1c00123
Web address : https://doi.org/10.1021/acsomega.1c00123
Self-archived copy’s web address: https://research.utu.fi/converis/portal/Publication/59142287
Of the three enzymes in the human cytochrome P450 family 1, CYP1A2 is an important enzyme mediating metabolism of xenobiotics including drugs in the liver, while CYP1A1 and CYP1B1 are expressed in extrahepatic tissues. Currently used CYP substrates, such as 7-ethoxycoumarin and 7-ethoxyresorufin, are oxidized by all individual CYP1 forms. The main aim of this study was to find profluorescent coumarin substrates that are more selective for the individual CYP1 forms. Eleven 3-phenylcoumarin derivatives were synthetized, their enzyme kinetic parameters were determined, and their interactions in the active sites of CYP1 enzymes were analyzed by docking and molecular dynamic simulations. All coumarin derivatives and 7-ethoxyresorufin and 7-pentoxyresorufin were oxidized by at least one CYP1 enzyme. 3-(3-Methoxyphenyl)-6-methoxycoumarin (19) was 7-O-demethylated by similar high efficiency [21-30 ML/(min.mol CYP)] by all CYP1 forms and displayed similar binding in the enzyme active sites. 3-(3-Fluoro-4-acetoxyphenyl)coumarin (14) was selectively 7-O-demethylated by CYP1A1, but with low efficiency [0.16 ML/(min mol)]. This was explained by better orientation and stronger H-bond interactions in the active site of CYP1A1 than that of CYP1A2 and CYP1B1. 3-(4-Acetoxyphenyl)-6-chlorocoumarin (20) was 7-O-demethylated most efficiently by CYP1B1 [53 ML/(min.mol CYP)], followed by CYP1A1 [16 ML/(min.mol CYP)] and CYP1A2 [0.6 ML/(min.mol CYP)]. Variations in stabilities of complexes between 20 and the individual CYP enzymes explained these differences. Compounds 14, 19, and 20 are candidates to replace traditional substrates in measuring activity of human CYP1 enzymes.
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