| Autor: |
Jones S; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA.; Department of Physics and Department of Biological Sciences, University of Arkansas Fay etteville , Fayetteville , AR , USA., Yarbrough AL; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA.; Department of Biology, University of Arkansas Little Rock , Little Rock , AR , USA., Shoeib A; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA., Bush JM; Department of Biology, University of Arkansas Little Rock , Little Rock , AR , USA., Fantegrossi WE; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA., Prather PL; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA., Radominska-Pandya A; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA., Fujiwara R; Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA. |
| Abstrakt: |
Recently, there has been a rise in abuse of synthetic cannabinoids (SCBs). The consumption of SCBs results in various effects and can induce toxic reactions, including paranoia, seizures, tachycardia and even death. 1-Naphthyl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate (FDU-PB-22) is a third generation SCB whose metabolic pathway has not been fully characterized. In this study, we conducted in vitro pharmacokinetic analysis of FDU-PB-22 metabolism. Metabolic reactions containing FDU-PB-22 and human liver microsomes (HLMs) were independent of NADPH but not UDP-glucuronic acid (UDPGA), suggesting that UDP-glucuronosyltransferases (UGTs) are the primary enzymes involved in this metabolism. It was further determined that the metabolite extensively formed after incubating FDU-PB-22 with UDPGA in HLMs was the glucuronide of FDU-PB-22 3-carboxyindole (FBI-COOH). Various hepatic UGTs showed enzymatic activity for FBI-COOH. A series of UGT inhibitors showed moderate to strong inhibition of FBI-COOH-glucuronidation in HLMs, suggesting that multiple UGT isoforms are involved in FBI-COOH-glucuronidation in the liver. Interestingly, an extra-hepatic isoform, UGT1A10, exhibited the highest activity with a K m value of 38 µM and a V max value of 5.90 nmol/min/mg. Collectively, these results suggest that both genetic mutations of and the co-administration of inhibitors for FDU-PB-22-metabolizing UGTs will likely increase the risk of FDU-PB-22-induced toxicity. |
