TY - JOUR
T1 - Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol
T2 - Role of pentylresorcinol moiety
AU - Yamaori, Satoshi
AU - Okushima, Yoshimi
AU - Masuda, Kazufumi
AU - Kushihara, Mika
AU - Katsu, Takashi
AU - Narimatsu, Shizuo
AU - Yamamoto, Ikuo
AU - Watanabe, Kazuhito
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Cannabidiol
KW - Cytochrome P450 1A1
KW - Direct inhibition
KW - Pentylresorcinol
KW - Structural requirement
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U2 - 10.1248/bpb.b13-00183
DO - 10.1248/bpb.b13-00183
M3 - Article
C2 - 23811569
AN - SCOPUS:84880443644
SN - 0918-6158
VL - 36
SP - 1197
EP - 1203
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 7
ER -