Chimalakonda Krishna C, James Laura P, Radominska-Pandya Anna, Moran Jeffery H
Arkansas Department of Health, Public Health Laboratory, 201 S. Monroe Street, Little Rock, AR, 72205, USA.
Drug Metab Lett. 2013 Mar;7(1):34-8. doi: 10.2174/187231280701131211151523.
"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 α-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.
“K2”或“香料”是一种新型滥用药物，其中掺入了精神活性合成大麻素JWH - 018和AM2201。先前的研究已确定羟基化（OH）和羧基化（COOH）产物是主要的人体代谢物，动力学研究表明CYP2C9和 - 1A2是参与JWH - 018和AM2201氧化的主要肝脏细胞色素P450酶。本研究通过检验以下假设扩展了这些发现：CYP2C9和1A2选择性化学抑制剂磺胺苯吡唑（SFZ）和α - 萘黄酮（ANF）可阻断人肝微粒体（HLM）中JWH - 018和AM2201的氧化。在存在浓度不断增加的SFZ（0.5 - 50 μM）和ANF（0.1 - 5.0 μM）的情况下，观察到JWH - 018和AM2201氧化受到浓度依赖性抑制。使用奥美拉唑、奎尼丁和酮康唑未观察到代谢抑制作用。本文给出的结果进一步证明了CYP2C9和1A2介导的JWH - 018和AM2201氧化的重要性，以及这些酶具有多态性等位基因的人群中出现不良毒性的可能性。
