Comparison between human liver microsomes and the fungus Cunninghamella elegans for biotransformation of the synthetic cannabinoid JWH-424 having a bromo-naphthyl moiety analysed by high-resolution mass spectrometry
Comparison between human liver microsomes and the fungus Cunninghamella elegans for biotransformation of the synthetic cannabinoid JWH-424 having a bromo-naphthyl moiety analysed by high-resolution mass spectrometry
复制标题
DOI：
10.1007/s11419-022-00612-2
复制
发表时间：
2022-02
影响因子：
2.2
通讯作者：
Shimpei Watanabe;T. Iwai;Ritsuko Matsushita;Toshio Nakanishi;Unnikrishnan Kuzhiumparambil;S. Fu;Yasuo Seto
中科院分区：
文献类型：
--
作者：
Shimpei Watanabe;T. Iwai;Ritsuko Matsushita;Toshio Nakanishi;Unnikrishnan Kuzhiumparambil;S. Fu;Yasuo Seto
JWH-424（8-溴-1-萘基）（1-戊基-1H-吲哚-3-基）甲酮（8-bromo-1-naphthyl）（1-pentyl-1H-indol-3-yl）methanone）是一种合成大麻素，是合成大麻素JWH-018的溴代类似物。尽管与JWH-018结构相似，但人们对JWH-424（包括其代谢）知之甚少。本研究的目的是比较人肝微粒体（HLM）和真菌Cunninghamella elegans作为JWH-424的代谢催化剂，以更好地理解真菌在合成大麻素代谢中的特征作用。HLM孵育混合物用甲醇稀释，真菌孵育混合物用二氯甲烷提取，并在甲醇中重构，然后通过液相色谱-高分辨率质谱（LC-HRMS）进行分析。ResultsHLM孵育导致通过二氢二醇形成，羟基化，和/或ipso取代的溴与羟基产生10种代谢产物。真菌孵育导致生产的23代谢产物通过羧化，二氢二醇形成，羟基化，酮形成，glucosidation和/或sulfation.ConclusionsGenerally，HLM模型给人的代谢产物和结构类似物的代谢在一个类似的方式很好的预测。然而，HLM产生的主要羟基代谢物是在萘而不是戊基部分（JWH-018的主要羟基化位点）羟基化的代谢物。另一方面，真菌代谢产物主要在戊基部分进行羟基化。代谢差异表明有必要验证真实尿液样本中的人体代谢物，而H9和H10（羟基萘），H8（ipso取代），F22（羟基戊基）和F17（二羟基戊基）建议用于监测尿液分析中的JWH-424。
PurposeJWH-424, (8-bromo-1-naphthyl)(1-pentyl-1H-indol-3-yl)methanone, is a synthetic cannabinoid, which is a brominated analogue of JWH-018, one of the best-known synthetic cannabinoids. Despite the structural similarity to JWH-018, little is known about JWH-424 including its metabolism. The aim of the study was to compare human liver microsomes (HLM) and the fungusCunninghamella elegansas the metabolism catalysts for JWH-424 to better understand the characteristic actions of the fungus in the synthetic cannabinoid metabolism.MethodsJWH-424 was incubated with HLM for 1 h andCunninghamella elegansfor up to 72 h. The HLM incubation mixtures were diluted with methanol and fungal incubation mixtures were extracted with dichloromethane and reconstituted in methanol before analyses by liquid chromatography–high-resolution mass spectrometry (LC-HRMS).ResultsHLM incubation resulted in production of ten metabolites through dihydrodiol formation, hydroxylation, and/or ipso substitution of the bromine with a hydroxy group. Fungal incubation led to production of 23 metabolites through carboxylation, dihydrodiol formation, hydroxylation, ketone formation, glucosidation and/or sulfation.ConclusionsGenerally, HLM models give good predictions of human metabolites and structural analogues are metabolised in a similar fashion. However, major hydroxy metabolites produced by HLM were those hydroxylated at naphthalene instead of pentyl moiety, the major site of hydroxylation for JWH-018. Fungal metabolites, on the other hand, had undergone hydroxylation mainly at pentyl moiety. The metabolic disagreement suggests the necessity to verify the human metabolites in authentic urine samples, while H9 and H10 (hydroxynaphthalene), H8 (ipso substitution), F22 (hydroxypentyl), and F17 (dihydroxypentyl) are recommended for monitoring of JWH-424 in urinalysis.