Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol
| Autor: | Yoshimi Okushima, Kazuhito Watanabe, Satoshi Yamaori, Ikuo Yamamoto |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Mechanism-based inhibition
Cannabidivarin Stereochemistry CYP1A1 Structural requirement Ether Olivetol Toxicology Orcinol Inactivation law.invention Terpene Structure-Activity Relationship chemistry.chemical_compound law Cytochrome P-450 CYP1A1 polycyclic compounds medicine Animals Humans Cannabidiol Moiety heterocyclic compounds Enzyme Inhibitors Resorcinols General Medicine respiratory system digestive system diseases Enzyme Activation surgical procedures operative Biochemistry chemistry Recombinant DNA medicine.drug |
| Zdroj: | Chemico-Biological Interactions. 215:62-68 |
| ISSN: | 0009-2797 |
| DOI: | 10.1016/j.cbi.2014.03.007 |
| Popis: | We previously demonstrated that cannabidiol (CBD) was a potent mechanism-based inhibitor of human cytochrome P450 1A1 (CYP1A1). However, the moiety of CBD that contributes to the potent mechanism-based inhibition of human CYP1A1 remains unknown. Thus, the effects of compounds structurally related to CBD on CYP1A1 activity were examined with recombinant human CYP1A1 in order to characterize the structural requirements for potent inactivation by CBD. When preincubated in the presence of NADPH for 20 min, olivetol, which corresponds to the pentylresorcinol moiety of CBD, enhanced the inhibition of the 7-ethoxyresorufin O-deethylase activity of CYP1A1. In contrast, d-limonene, which corresponds to the terpene moiety of CBD, failed to inhibit CYP1A1 activity in a metabolism-dependent manner. Pentylbenzene, which lacks two free phenolic hydroxyl groups, also did not enhance CYP1A1 inhibition. On the other hand, preincubation of the CBD-2′-monomethyl ether (CBDM) and CBD-2′,6′-dimethyl ether (CBDD) enhanced the inhibition of CYP1A1 activity. Inhibition by cannabidivarin (CBDV), which possessed a propyl side chain, was strongly potentiated by its preincubation. Orcinol, which has a methyl group, augmented CYP1A1 inhibition, whereas its derivative without an alkyl side chain, resorcinol, did not exhibit any metabolism-dependent inhibition. The preincubation of CBD-hydroxyquinone did not markedly enhance CYP1A1 inhibition. We further confirmed that olivetol, CBDM, CBDD, CBDV, and orcinol, as well as CBD (kinact = 0.215 min−1), inactivated CYP1A1 activity; their kinact values were 0.154, 0.0638, 0.0643, 0.226, and 0.0353 min−1, respectively. These results suggest that the methylresorcinol structure in CBD may have structurally important roles in the inactivation of CYP1A1. Article CHEMICO-BIOLOGICAL INTERACTIONS.215:62-68(2014) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect