Synthetic
cannabinoids (SCBs), synonymous with 'K2', 'Spice' or 'synthetic marijuana', are
psychoactive drugs of abuse that frequently result in clinical effects and toxicity more severe than those classically associated with Δ9-tetrahydrocannabinol such as extreme agitation,
hallucinations,
supraventricular tachycardia,
syncope, and
seizures.
JWH-018 is one of the earliest compounds identified in various SCB products, and our laboratory previously demonstrated that
JWH-018 undergoes extensive metabolism by
cytochromes P450 (P450), binds to, and activates
cannabinoid receptors (CBRs). The major
enzyme involved in the metabolism of
JWH-018 is
CYP2C9, a highly polymorphic
enzyme found largely in the intestines and liver, with *1 being designated as the wild type, and *2 and *3 as the two most common variants. Three different major products have been identified in human urine and plasma:
JWH-018 (ω)-
OH,
JWH-018 (ω-1)-OH(R), and
JWH-018 (ω-1)-OH(S). The (ω-1)-OH metabolite of
JWH-018 is a chiral molecule, and is thus designated as either (ω-1)-OH(R) or (ω-1)-OH(S). Here, in vitro
enzyme kinetic assays performed with human recombinant
CYP2C9 variants (*1, *2, and *3) revealed that oxidative metabolism by
CYP2C9*3 resulted in significantly less formation of (ω)-
OH and (ω-1)-OH metabolites. Surprisingly,
CYP2C9*2 was roughly 3.6-fold more efficient as the
CYP2C9*1
enzyme based on Vmax/Km, increasing the rate of
JWH-018 metabolism and allowed for a much more rapid elimination. These results suggest that genetic polymorphisms of
P450 enzymes result in the production of varying levels of biologically active
JWH-018 metabolites in some individuals, offering a mechanistic explanation for the diverse clinical toxicity often observed following
JWH-018 abuse.