Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants.

Autor: Patton AL; Arkansas Department of Health, Arkansas Public Health Laboratory, 4815 W Markham St, Little Rock, AR, 72205, USA; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: amy.patton@pinpointtesting.com., Seely KA; Arkansas Department of Health, Arkansas Public Health Laboratory, 4815 W Markham St, Little Rock, AR, 72205, USA. Electronic address: Katie.Seely@arkansas.gov., Yarbrough AL; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: ALYarbrough@uams.edu., Fantegrossi W; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: WEFantegrossi@uams.edu., James LP; Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St #550, Little Rock, AR, 72205, USA. Electronic address: JamesLauraP@uams.edu., McCain KR; Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St #550, Little Rock, AR, 72205, USA. Electronic address: MccainKeith@uams.edu., Fujiwara R; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: rfujiwara@uams.edu., Prather PL; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: pratherpaull@uams.edu., Moran JH; Arkansas Department of Health, Arkansas Public Health Laboratory, 4815 W Markham St, Little Rock, AR, 72205, USA. Electronic address: jeff.moran@pinpointtesting.com., Radominska-Pandya A; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, USA. Electronic address: radominskaanna@uams.edu.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2018 Apr 06; Vol. 498 (3), pp. 597-602. Date of Electronic Publication: 2018 Mar 10.
DOI: 10.1016/j.bbrc.2018.03.028
Abstrakt: 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 Δ 9 -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 V max /K m , 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.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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