Insights into the Cardiotoxic Effects of Alkaloids: Pilot Study

Overview

Journal Toxins (Basel)

Publisher MDPI

Specialty Toxicology

Date 2022 Jul 25

PMID 35878228

Authors

Amir Taldaev

Roman P Terekhov

Elizaveta V Melnik

Maria V Belova

Sergey V Kozin

Andrey A Nedorubov

Tatyana Ya Pomerantseva

Galina V Ramenskaya

Affiliations

Soon will be listed here.

Abstract

Jervine, protoveratrine A (proA), and protoveratrine B (proB) are alkaloids that are presented in some remedies obtained from , such as . This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel Na1.5, and machine learning-based structure-activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (-10.8 kcal/mol), logP value (4.188), and p value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC. In general, all three analyzed alkaloids show the affinity to Na1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by Na1.5 inhibition.

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References

Serdoz L, Rittger H, Furlanello F, Bastian D . Quinidine-A legacy within the modern era of antiarrhythmic therapy. Pharmacol Res. 2019; 144:257-263. DOI: 10.1016/j.phrs.2019.04.028. View

Liang Y, Wu J, Leung E, Zhou H, Liu Z, Yan G . Identification of Oxygenated Fatty Acid as a Side Chain of Lipo-Alkaloids in Aconitum carmichaelii by UHPLC-Q-TOF-MS and a Database. Molecules. 2016; 21(4):437. PMC: 6273321. DOI: 10.3390/molecules21040437. View

Yakan S, Aydin T, Gulmez C, Ozden O, Erdogan K, Daglioglu Y . The protective role of jervine against radiation-induced gastrointestinal toxicity. J Enzyme Inhib Med Chem. 2019; 34(1):789-798. PMC: 6419660. DOI: 10.1080/14756366.2019.1586681. View

Grube S, Langguth P, Junginger H, Kopp S, Midha K, Shah V . Biowaiver monographs for immediate release solid oral dosage forms: quinidine sulfate. J Pharm Sci. 2008; 98(7):2238-51. DOI: 10.1002/jps.21606. View

Kooistra B, Dijkman B, Einhorn T, Bhandari M . How to design a good case series. J Bone Joint Surg Am. 2009; 91 Suppl 3:21-6. DOI: 10.2106/JBJS.H.01573. View

Stieger B, Meier P . Pharmacogenetics of drug transporters in the enterohepatic circulation. Pharmacogenomics. 2011; 12(5):611-31. DOI: 10.2217/pgs.11.53. View

Grobosch T, Binscheck T, Martens F, Lampe D . Accidental intoxication with Veratrum album. J Anal Toxicol. 2008; 32(9):768-73. DOI: 10.1093/jat/32.9.768. View

Chen J, Wen B, Wang Y, Wu S, Zhang X, Gu Y . Jervine exhibits anticancer effects on nasopharyngeal carcinoma through promoting autophagic apoptosis via the blockage of Hedgehog signaling. Biomed Pharmacother. 2020; 132:110898. DOI: 10.1016/j.biopha.2020.110898. View

Li Q, Yang K, Zhao Y, Qin X, Yang X, Liu L . Potent anti-inflammatory and analgesic steroidal alkaloids from Veratrum taliense. J Ethnopharmacol. 2016; 179:274-9. DOI: 10.1016/j.jep.2015.12.059. View

10.

Melnik E, Belova M, Potskhveriya M, Simonova A, Tyurin I, Ramenskaya G . Veratrum Alkaloid Determination in Four Cases of Veratrum Aqua Poisonings. J Anal Toxicol. 2021; 46(1):e42-e47. DOI: 10.1093/jat/bkab019. View

11.

Forrester J, Price J, Holstege C . Intoxication with a ramp (Allium tricocca) mimicker. False hellebore (Veratrum viride) ingestion. Wilderness Environ Med. 2010; 21(1):61-3. DOI: 10.1016/j.wem.2009.12.004. View

12.

Veerman C, Wilde A, Lodder E . The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology. Gene. 2015; 573(2):177-87. PMC: 6636349. DOI: 10.1016/j.gene.2015.08.062. View

13.

Vicentini C, Manfredini S, Contini C . Ancient treatment for lice: a source of suggestions for carriers of other infectious diseases?. Infez Med. 2018; 26(2):181-192. View

14.

Malik O, Kaye A, Kaye A, Belani K, Urman R . Emerging roles of liposomal bupivacaine in anesthesia practice. J Anaesthesiol Clin Pharmacol. 2017; 33(2):151-156. PMC: 5520585. DOI: 10.4103/joacp.JOACP_375_15. View

15.

Srinivasan P, Smolke C . Biosynthesis of medicinal tropane alkaloids in yeast. Nature. 2020; 585(7826):614-619. PMC: 7529995. DOI: 10.1038/s41586-020-2650-9. View

16.

Sun J, Jeliazkova N, Chupakin V, Golib-Dzib J, Engkvist O, Carlsson L . ExCAPE-DB: an integrated large scale dataset facilitating Big Data analysis in chemogenomics. J Cheminform. 2017; 9:17. PMC: 5340785. DOI: 10.1186/s13321-017-0203-5. View

17.

Forli S, Huey R, Pique M, Sanner M, Goodsell D, Olson A . Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc. 2016; 11(5):905-19. PMC: 4868550. DOI: 10.1038/nprot.2016.051. View

18.

Rauber-Luthy C, Halbsguth U, Kupferschmidt H, Konig N, Megevand C, Zihlmann K . Low-dose exposure to Veratrum album in children causes mild effects--a case series. Clin Toxicol (Phila). 2010; 48(3):234-7. DOI: 10.3109/15563650903575243. View

19.

Wong V, Law B, Yao X, Chen X, Xu S, Liu L . Advanced research technology for discovery of new effective compounds from Chinese herbal medicine and their molecular targets. Pharmacol Res. 2016; 111:546-555. DOI: 10.1016/j.phrs.2016.07.022. View

20.

Gu W, Li N, Leung E, Zhou H, Yao X, Liu L . Rapid identification of new minor chemical constituents from Smilacis Glabrae Rhizoma by combined use of UHPLC-Q-TOF-MS, preparative HPLC and UHPLC-SPE-NMR-MS techniques. Phytochem Anal. 2015; 26(6):428-35. DOI: 10.1002/pca.2577. View