uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Investigations on the relationship between structural properties of carboxylic acids and the tendency of forming CoA conjugates
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2016 (English)Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Formation of reactive metabolites that are capable of binding covalently to endogenous proteins and cause cellular dysfunction is considered a key mechanism in idiosyncratic adverse drug reactions. Carboxylic acid drugs have been associated with idiosyncratic hepatotoxicity and can form xenobiotic-S-acyl-coenzyme A thioesters (CoA conjugates), a reaction catalyzed by acyl-coenzyme A synthetases (ACSs). The overall aim of this project is to evaluate if there is a relationship between structural properties of carboxylic acids and the tendency of forming potentially reactive CoA conjugates.

In vitro method using human liver microsomes supplemented with coenzyme A and ATP was applied to study formation of CoA conjugates. Metabolites were identified using reversed phase UPLC-Q-ToF MS. Conditions used for termination of the reaction and during Q-ToF MS analysis were optimized. Time- and concentration-dependent formation was studied and Kvalues (indicative of the enzyme-substrate affinity) were estimated fitting data to the Michaelis-Menten equation. 

Eight out of 20 incubated compounds (ibufenac, ibuprofen, (S)-AZD6610, (R)-AZD6610, 3-phenylpropionoic acid, α-methylhydrocinnamic acid, 2-fluoro-3-phenylpropanoic acid and 5-phenylvaleric acid) formed CoA conjugates. Kwas estimated to: 200±19 µM for ibufenac, >960 µM for ibuprofen, 92±11 µM for 3-phenylpropionic acid, 120±19 µM for α-methylhydrocinnamic acid and 740±82 µM for 5-phenylvaleric acid. Results show that increasing the substitution at the α-carbon of carboxylic acids decreases the affinity for microsomal ACSs and that there is a relationship between structural properties of carboxylic acids and the tendency of forming CoA conjugates. 

Place, publisher, year, edition, pages
2016. , 56 p.
Keyword [en]
carboxylic acids, coenzyme A, conjugation, relationship
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-273738OAI: oai:DiVA.org:uu-273738DiVA: diva2:896055
External cooperation
AstraZeneca R&D
Subject / course
Toxicology
Educational program
Master of Science Programme in Pharmacy
Supervisors
Examiners
Available from: 2016-10-06 Created: 2016-01-18 Last updated: 2016-10-06Bibliographically approved

Open Access in DiVA

No full text

By organisation
Department of Pharmaceutical Biosciences
Pharmacology and Toxicology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 163 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf