Skip to Main content Skip to Navigation
Theses

Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses

Abstract : Without crystal structures to study the CYP26 family of drug metabolizing enzymes, homology models were used to characterize CYP26A1, CYP26B1 and CYP26C1 and to identify substrates and inhibitors of the enzymes. Computational models of each isoform based on structural homology to CYP120 were validated by docking all-trans retinoic acid, an endogenous ligand of CYP26. Docking of retinoic acid receptor agonists and antagonists suggested that tazarotenic acid (TA) and adapalene may be metabolic substrates for CYP26, data which was confirmed using in vitro metabolite identification assays. Phenotyping experiments determined that CYP26s played a major role in the metabolism of these compounds in vitro. The kinetics of TA sulfoxidation by CYP26A1 and CYP26B1 were characterized and the compound was proposed as an in vitro probe of CYP26 activity in single enzyme expression systems. Structural characterization efforts identified similarities between the CYP26 homology models and the known crystal structure of CYP2C8, in agreement with previously published reports. Using TA as a probe, the IC50’s of known CYP2C8 inhibitors was measured against CYP26A1 and CYP26B1, with a statistically significant correlation observed between CYP26A1 and CYP2C8. Additional in vitro and computational experiments were used to characterize the inhibition mechanism for the most potent inhibitors. The observed in vitro inhibition was then used to predict the likelihood of CYP26 inhibition being involved in clinically relevant drug interactions. As a whole, the results presented support the role of the CYP26s in the metabolism of xenobiotic compounds as well as in potential in vivo drug interactions.
Document type :
Theses
Complete list of metadatas

Cited literature [171 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-01376678
Contributor : Abes Star :  Contact
Submitted on : Wednesday, October 5, 2016 - 2:29:55 PM
Last modification on : Monday, October 12, 2020 - 10:28:26 AM
Long-term archiving on: : Friday, January 6, 2017 - 1:35:25 PM

File

2016NICE4033.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01376678, version 1

Collections

Citation

Robert Foti. Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses. Agricultural sciences. Université Nice Sophia Antipolis, 2016. English. ⟨NNT : 2016NICE4033⟩. ⟨tel-01376678⟩

Share

Metrics

Record views

1126

Files downloads

697