Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids

Inhibitory effects of D9-tetrahydrocannabinol (D9-THC), cannabidiol (CBD), and cannabinol (CBN) on the catalytic activities of human recombinant cytochrome P450 (CYP) 2A6 and CYP2B6 were investigated. D9-THC, CBD, and CBN noncompetitively inhibited coumarin 7-hydroxylase activity of recombinant CYP2A6 with the apparent Ki values of 28.9, 55.0, and 39.8 lM, respectively. On the other hand, D9-THC, CBD, and CBN inhibited 7-benzoxyresorufin O-debenzylase activity of recombinant CYP2B6 in a mixed fashion with the Ki values of 2.81, 0.694, and 2.55 lM, respectively. Because the inhibition of CYP2B6 by CBD was the most potent, investigation was conducted to determine which moiety of the CBD structure was responsible for the inhibition. Olivetol and d-limonene, the partial structure of CBD, inhibited the CYP2B6 activity to some extent. Inhibitory effects of CBD-20-monomethyl ether and CBD-20,60- dimethyl ether attenuated with the number of methylations on the phenolic hydroxyl groups in the resorcinol moiety of CBD. Cannabidivarin, a CBD analogue having a propyl side chain, inhibited the CYP2B6 activity less potently than CBD possessing a pentyl side chain. Therefore, both structures of pentylresorcinol and terpene moieties of CBD were suggested to play important roles in the CYP2B6 inhibition. D9-THC, CBD, and CBN showed metabolismdependent inhibition for CYP2A6 but not for CYP2B6. Furthermore, D9-THC and CBN were characterized as mechanism-based inhibitors for CYP2A6. The kinact and KI values of D9-THC were 0.0169 min-1 and 0.862 lM, respectively; the kinact and KI values of CBN were 0.00909 min-1 and 1.01 lM, respectively. These results indicated that D9-THC, CBD, and CBN showed differential inhibition against CYP2A6 and CYP2B6.