title: Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes.
abstract: BACKGROUND
  Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
  
  
  RESULTS
  The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67%∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression, and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine.
  
  
  CONCLUSIONS
  Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Republic of Singapore; Cardiovascular & Metabolic Disorders Program, DUKE-NUS Graduate Medical School Singapore, Singapore, Republic of Singapore.
authors.forename: Heming
authors.initials: H
authors.lastname: Wei
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
authors.forename: Mohd Fadzly Amar
authors.initials: MF
authors.lastname: Jamil
authors.affiliation: Malaysian Institute of Pharmaceuticals & Nutraceuticals. Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia; Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Tan
authors.affiliation: Malaysian Institute of Pharmaceuticals & Nutraceuticals. Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia.
authors.forename: Mohd Ilham
authors.initials: MI
authors.lastname: Adenan
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Republic of Singapore; Cardiovascular & Metabolic Disorders Program, DUKE-NUS Graduate Medical School Singapore, Singapore, Republic of Singapore.
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.affiliation: National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Republic of Singapore; Cardiovascular & Metabolic Disorders Program, DUKE-NUS Graduate Medical School Singapore, Singapore, Republic of Singapore.
authors.forename: Winston
authors.initials: W
authors.lastname: Shim
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D019666:Rubiaceae / Q000737:chemistry*; D046948:Secologanin Tryptamine Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity*
chemical_list: D051668:Delayed Rectifier Potassium Channels; D046948:Secologanin Tryptamine Alkaloids; C001801:mitragynine