Harmaline and harmine areβ-carboline alkaloids with effective pharmacological effects.Harmaline can be transformed into harmine after oral administration.However,enzymes involved in the metabolic pathway remain uncle...Harmaline and harmine areβ-carboline alkaloids with effective pharmacological effects.Harmaline can be transformed into harmine after oral administration.However,enzymes involved in the metabolic pathway remain unclear.In this study,harmaline was incubated with rat liver microsomes(RLM),rat brain microsomes(RBM),blood,plasma,broken blood cells,and heme peroxidases including horseradish peroxidase(HRP),lactoperoxidase(LPO),and myeloperoxidase(MPO).The production of harmine was determined by a validated UPLC-ESI-MS/MS method.Results showed that heme peroxidases catalyzed the oxidative dehydrogenation of harmaline.All the reactions were in accordance with the Hill equation.The reaction was inhibited by ascorbic acid and excess H_(2)0_(2).The transformation of harmaline to harmine was confirmed after incubation with blood,plasma,and broken blood cells,rather than RLM and RBM.Harmaline was incubated with blood,plasma,and broken cells liquid for 3 h,and the formation of harmine became stable.Results indicated an integrated metabolic pathway of harmaline,which will lay foundation for the oxidation reaction of dihydro-P-carboline.Moreover,the metabolic stability of harmaline in blood should not be ignored when the pharmacokinetics study of harmaline is carried out.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82173885 and 81872933)the National Natural Science Foundation of Xinjiang Uyghur Autonomous Region of China(No.U1130303)+1 种基金the Technology Cooperation Projects of Science in Shanghai,China(No.20015800100)the Key Laboratory Open Project of Xinjiang Uyghur Autonomous Region(No.2019D04018).
文摘Harmaline and harmine areβ-carboline alkaloids with effective pharmacological effects.Harmaline can be transformed into harmine after oral administration.However,enzymes involved in the metabolic pathway remain unclear.In this study,harmaline was incubated with rat liver microsomes(RLM),rat brain microsomes(RBM),blood,plasma,broken blood cells,and heme peroxidases including horseradish peroxidase(HRP),lactoperoxidase(LPO),and myeloperoxidase(MPO).The production of harmine was determined by a validated UPLC-ESI-MS/MS method.Results showed that heme peroxidases catalyzed the oxidative dehydrogenation of harmaline.All the reactions were in accordance with the Hill equation.The reaction was inhibited by ascorbic acid and excess H_(2)0_(2).The transformation of harmaline to harmine was confirmed after incubation with blood,plasma,and broken blood cells,rather than RLM and RBM.Harmaline was incubated with blood,plasma,and broken cells liquid for 3 h,and the formation of harmine became stable.Results indicated an integrated metabolic pathway of harmaline,which will lay foundation for the oxidation reaction of dihydro-P-carboline.Moreover,the metabolic stability of harmaline in blood should not be ignored when the pharmacokinetics study of harmaline is carried out.
