CYP2C9 drives Δ8-THC conversion to its psychoactive 11-hydroxy metabolite
- In human liver microsomes, Δ8-THC gave several monohydroxylated products, led by the psychoactive 11-hydroxy metabolite; CYP2C9 emerged as main producer.
- Ring hydroxylation came mainly from CYP3A, side-chain oxidation from CYP2D6, CYP1A2 and CYP3A4.
- CYP2C9 handled Δ8-THC less efficiently than Δ9-THC, though C11 hydroxylation matters more for Δ8; loss-of-function genotypes were predicted to sharply cut 11-hydroxy formation, moving clearance to CYP3A4/CYP2C19.
💡 Points
Microsomes can tell you which enzyme makes the psychoactive metabolite; they can't tell you how a person's exposure will split. They give no in vivo exposure to the 11-hydroxy species, and the genotype effect is a prediction, not an observation. Clinical PK in CYP2C9 poor metabolizers, plus 2C9 inhibitor interaction data, would have to come before anyone calls this a risk factor.
Characterization of Cytochrome P450-Mediated Metabolism of Δ8-tetrahydrocannabinol in vitro ↗