Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol

Role of pentylresorcinol moiety

Satoshi Yamaori, Yoshimi Okushima, Kazufumi Masuda, Mika Kushihara, Takashi Katsu, Shizuo Narimatsu, Ikuo Yamamoto, Kazuhito Watanabe

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined. However, the mechanism underlying this CBD inhibition remains to be clarified. Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity were investigated with recombinant human CYP1A1. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, inhibited the 7-ethoxyresorufin O-deethylase activity of CYP1A1; its inhibitory effect (IC50=13.8 μm) was less potent than that of CBD (IC 50=0.355 μm). In contrast, d-limonene, which corresponds to the terpene moiety of CBD, only slightly inhibited CYP1A1 activity. CBD-2'-monomethyl ether (CBDM) and CBD-2',6'- dimethyl ether inhibited CYP1A1 activity with IC50 values of 4.07 and 23.0 μm, respectively, indicating that their inhibitory effects attenuated depending on the level of methylation on the free phenolic hydroxyl groups in the pentylresorcinol moiety of CBD. Cannabidivarin inhibited CYP1A1 activity, although its inhibitory potency (IC50=1.85 μm) was lower than that of CBD. The inhibitory effects of Δ9-tetrahydrocannabinol and cannabielsoin (IC 50s ≈10 μm), which contain a free phenolic hydroxyl group and are structurally constrained, were less potent than that of CBDM, which contains a free phenolic hydroxyl group and is rotatable between pentylresorcinol and terpene moieties. These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.

Original languageEnglish
Pages (from-to)1197-1203
Number of pages7
JournalBiological and Pharmaceutical Bulletin
Volume36
Issue number7
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Cannabidiol
Cytochrome P-450 Enzyme System
Hydroxyl Radical
Inhibitory Concentration 50
Cytochrome P-450 CYP1A1
Terpenes
Dronabinol
Ether
Methylation

Keywords

  • Cannabidiol
  • Cytochrome P450 1A1
  • Direct inhibition
  • Pentylresorcinol
  • Structural requirement

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Pharmacology

Cite this

Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol : Role of pentylresorcinol moiety. / Yamaori, Satoshi; Okushima, Yoshimi; Masuda, Kazufumi; Kushihara, Mika; Katsu, Takashi; Narimatsu, Shizuo; Yamamoto, Ikuo; Watanabe, Kazuhito.

In: Biological and Pharmaceutical Bulletin, Vol. 36, No. 7, 07.2013, p. 1197-1203.

Research output: Contribution to journalArticle

Yamaori, S, Okushima, Y, Masuda, K, Kushihara, M, Katsu, T, Narimatsu, S, Yamamoto, I & Watanabe, K 2013, 'Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: Role of pentylresorcinol moiety', Biological and Pharmaceutical Bulletin, vol. 36, no. 7, pp. 1197-1203. https://doi.org/10.1248/bpb.b13-00183
Yamaori, Satoshi ; Okushima, Yoshimi ; Masuda, Kazufumi ; Kushihara, Mika ; Katsu, Takashi ; Narimatsu, Shizuo ; Yamamoto, Ikuo ; Watanabe, Kazuhito. / Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol : Role of pentylresorcinol moiety. In: Biological and Pharmaceutical Bulletin. 2013 ; Vol. 36, No. 7. pp. 1197-1203.
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