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dc.contributor.authorJuvonen, RO
dc.contributor.authorRauhamäki, S
dc.contributor.authorKortet, S
dc.contributor.authorNiinivehmas, S
dc.contributor.authorTroberg, J
dc.contributor.authorPetsalo, A
dc.contributor.authorHuuskonen, J
dc.contributor.authorRaunio, H
dc.contributor.authorFinel, M
dc.contributor.authorPentikäinen, OT
dc.date.accessioned2018-08-28T08:21:33Z
dc.date.available2018-08-28T08:21:33Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6857
dc.description.abstractIntestinal and hepatic glucuronidation by the UDP-glucuronosyltransferases (UGTs) greatly affect the bioavailability of phenolic compounds. UGT1A10 catalyzes glucuronidation reactions in the intestine, but not in the liver. Here, our aim was to develop selective, fluorescent substrates to easily elucidate UGT1A10 function. To this end, homology models were constructed and used to design new substrates, and subsequently, six novel C3-substituted (4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-(dimethylamino)phenyl, 4-methylphenyl, or triazole) 7-hydroxycoumarin derivatives were synthesized from inexpensive starting materials. All tested compounds could be glucuronidated to nonfluorescent glucuronides by UGT1A10, four of them highly selectively by this enzyme. A new UGT1A10 mutant, 1A10-H210M, was prepared on the basis of the newly constructed model. Glucuronidation kinetics of the new compounds, in both wild-type and mutant UGT1A10 enzymes, revealed variable effects of the mutation. All six new C3-substituted 7-hydroxycoumarins were glucuronidated faster by human intestine than by liver microsomes, supporting the results obtained with recombinant UGTs. The most selective 4-(dimethylamino)phenyl and triazole C3-substituted 7-hydroxycoumarins could be very useful substrates in studying the function and expression of the human UGT1A10.
dc.language.isoenglanti
dc.publisherAmerican Chemical Society (ACS)
dc.relation.ispartofseriesMolecular Pharmaceutics
dc.relation.urihttp://dx.doi.org/10.1021/acs.molpharmaceut.7b00871
dc.rightsCC BY http://creativecommons.org/licenses/by/4.0/
dc.subject7-hydroxycoumarin derivative
dc.subjectdrug metabolism
dc.subjectfluorescence
dc.subjectin silico
dc.subjectUDP-glucuronosyltransferase
dc.titleMolecular Docking-Based Design and Development of a Highly Selective Probe Substrate for UDP-glucuronosyltransferase 1A10
dc.description.versionpublished version
dc.contributor.departmentSchool of Pharmacy, Activities
uef.solecris.id52724465en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© American Chemical Society
dc.relation.doi10.1021/acs.molpharmaceut.7b00871
dc.description.reviewstatuspeerReviewed
dc.format.pagerange923-933
dc.relation.issn1543-8384
dc.relation.issue3
dc.relation.volume15
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


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