Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity.

Autor: Pinson A; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA. Electronic address: apinson@harding.edu., Yarbrough AL; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA; Department of Biology, University of Arkansas Little Rock, 2801 S. University Ave., Little Rock, AR 72204, USA. Electronic address: alyarbrough@ualr.edu., Bush JM; Department of Biology, University of Arkansas Little Rock, 2801 S. University Ave., Little Rock, AR 72204, USA. Electronic address: jmbush@ualr.edu., Cabanlong CV; 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: ccabanlong@uams.edu., Shoeib A; 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: amshoeib@uams.edu., Jackson BK; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA. Electronic address: bjackson4@uams.edu., Fukuda S; 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: sfukuda@uams.edu., Gogoi J; 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: jgogoi@uams.edu., Fantegrossi WE; 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., McCain K; Department of Pharmacy Practice, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA. Electronic address: mccainkeith@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., Fujiwara R; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA. Electronic address: rfujiwara@uams.edu., Radominska-Pandya A; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR 72205, USA. Electronic address: radominskaanna@uams.edu.
Jazyk: angličtina
Zdroj: Pharmacology, biochemistry, and behavior [Pharmacol Biochem Behav] 2020 Aug; Vol. 195, pp. 172949. Date of Electronic Publication: 2020 May 13.
DOI: 10.1016/j.pbb.2020.172949
Abstrakt: AKB48 and its fluorinated derivative 5F-AKB48 are synthetic cannabinoids (SCs) which have caused hospitalizations and deaths in human users. Abuse of SCs is dangerous because users may mistake them for natural cannabis, which is generally considered to be unlikely to elicit adverse effects. The present studies were designed to investigate the in vitro oxidative metabolism of 5F-AKB48 by human microsomal fractions from different organs and sexes as well as recombinant human cytochrome P450s (P450s). Mass spectrometry data tentatively provides evidence for the existence of mono-, di-, and trihydroxylated metabolites in a successive metabolism. Experiments utilizing P450s revealed that the most active enzymes (CYP2D6, CYP2J2, CYP3A4, and CYP3A5) effectively produced mono- and dihydroxylated metabolites, while CYP3A4/5 also produced significant amounts of the trihydroxylated metabolite. Moreover, although the affinity and potency of Phase I metabolite 4OH-5F-AKB48 is reduced when compared to that of the parent drug, this metabolite nevertheless retains similar high affinity for CB1 receptors, and greater efficacy for G protein activation, when compared to THC. Finally, 5F-AKB48 produced time- and dose-dependent cannabimimetic effects in mice which were more potent, but shorter acting, than those of Δ 9 -THC, and were attenuated by prior treatment with the CB1 antagonist rimonabant. Based on our data, we hypothesize that while many cases of toxicity result from genetic mutations, which can lead to a decrease or even absence of activity for Phase I drug-metabolizing enzymes, other P450s could potentially increase their role in the metabolism of these SCs. Because many metabolites of SCs remain biologically active, they could contribute to the deleterious effects of these substances.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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