“K2” or “Spice” is an emerging drug of abuse that is laced with psychoactive synthetic cannabinoids JWH-018
and AM2201. Previous studies have identified hydroxylated (OH) and carboxylated (COOH) species as primary human
metabolites, and kinetic studies have implicated CYP2C9 and -1A2 as major hepatic P450s involved in JWH-018 and
AM2201 oxidation. The present study extends these findings by testing the hypothesis that CYP2C9- and 1A2-selective
chemical inhibitors, sulfaphenazole (SFZ) and -naphthoflavone (ANF), block oxidation of JWH-018 and AM2201 in
human liver microsomes (HLM). A concentration-dependent inhibition of JWH-018 and AM2201 oxidation was observed
in the presence of increasing concentration of SFZ (0.5 – 50 μM) and ANF (0.1 – 5.0 μM). No metabolic inhibition was
observed with omeprazole, quinidine, and ketoconazole. The results presented herein further demonstrate the importance
of CYP2C9- and 1A2-mediated oxidation of JWH-018 and AM2201 and the likelihood of adverse toxicity in populations
with polymorphic alleles of these enzymes.
Keywords: AM2201, Cytochrome P450, JWH-018, K2/Spice, Synthetic cannabinoids.
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