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Functional consequences of synthetic cannabinoid metabolites and CYP2C9 polymorphisms (838.4)
Author(s) -
Allen Catherine,
Patton Amy,
Seely Kathryn,
Fantegrossi William,
RadominskaPandya Anna,
Prather Paul,
Ford Benjamin,
James Laura,
Moran Jeffery
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.838.4
Subject(s) - cyp2c9 , cannabinoid , pharmacology , metabolite , cannabinoid receptor , chemistry , cytochrome p450 , rimonabant , enzyme , receptor , biochemistry , antagonist , biology
Synthetic cannabinoid (SC) abuse is a growing problem. Previous studies using recombinant cytochrome P450 (CYP) enzymes identified CYP2C9 as an isozyme responsible for SC oxidation, but the role of genetic variability in SC metabolism has not been studied. To examine the relationship of CYP2C9 polymorphisms and SC effects, mice were treated with JWH‐018 or the chiral (ω‐1)‐hydroxyl metabolite ((ω‐1)‐OH) that is formed via CYP2C9 action. Administration of JWH‐018 (i.p. 3 mg/kg) produced Δ 9 ‐THC‐like effects on core temperature and locomotor activity in mice that corresponded to brain concentrations of 10 ng/g for JWH‐018 and 2 ng/g for ( R/S)‐ (ω‐1)‐OH. Administration of purified ( R) ‐ or ( S) ‐(ω‐1)‐OH enantiomers (i.p. 3 mg/kg) equally reduced locomotor activity and core temperature in the mice. Pre‐treatment with the cannabinoid receptor‐1 antagonist rimonabant attenuated the physiologic effects associated with administration of the chiral (ω‐1)‐OH metabolites. Both enantiomers also retained nanomolar affinity and intrinsic activity at cannabinoid receptors. In vitro enzyme kinetic assays performed using human recombinant CYP2C9 variants (*1, *2, and *3) showed reduced metabolite formation with the CYP2C9*3 variant. Thus, data demonstrate comparable biologic activity for the chiral (ω‐1)‐OH metabolites of CYP2C9 and suggest a potential role for CYP2C9 polymorphisms as a modulator of drug toxicity. Grant Funding Source : Supported by NIH grants RR020146 and RR029884 and an institutional ASPET SURF award.