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The Natural Products Journal

Editor-in-Chief

ISSN (Print): 2210-3155
ISSN (Online): 2210-3163

Mini-Review Article

Metabolites Study of Experimental Plant Derived Alkaloids: A Review

Author(s): Kuntal Manna, Waikhom Somraj Singh, Sanchari Goswami, Abu Md Ashif Ikbal, Amlanjyoti Rajkhowa and Bikash Debnath*

Volume 13, Issue 7, 2023

Published on: 09 March, 2023

Article ID: e300123213242 Pages: 15

DOI: 10.2174/2210315513666230130093453

Price: $65

Abstract

Alkaloids are waste products of plant metabolic processes, containing at least one nitrogen atom in the heterocyclic ring. They serve a wide variety of physiological functions in humans and animals. Metabolism plays a central role in regulating the toxicity of various phytochemicals. Available literature of biological sources and metabolism study of pyrrolidine, pyrrolizidine, pyridine, quinoline, isoquinoline, phenanthrene, phenethylamine, indole, terpenoid, and aporphine groups of experimental plantsderived alkaloids were collected from the Google Scholar, PubMed/Medline, Science Direct, Scopus, Wiley Online Library, and Web of Science search engines. The literature reveals that hepatic microsomal enzymes such as monooxygenase and putative NADPH-FMN-reductase, carboxyl esterase, CYP2B6, CYP3A4, and CYP2D6 are primarily involved in the metabolism of alkaloids. This review may encourage natural product researchers to further research and develop new plant-derived alkaloidal drugs.

Graphical Abstract

[1]
Jing, H.; Liu, J.; Liu, H.; Xin, H. Histochemical investigation and kinds of alkaloids in leaves of different developmental stages in Thymus quinquecostatus. Sci. World J., 2014, 2014, 839548.
[http://dx.doi.org/10.1155/2014/839548] [PMID: 25101324]
[2]
Yang, L.; Stöckigt, J. Trends for diverse production strategies of plant medicinal alkaloids. Nat. Prod. Rep., 2010, 27(10), 1469-1479.
[http://dx.doi.org/10.1039/c005378c] [PMID: 20730220]
[3]
Aniszewski, T. Alkaloids-Secrets of Life: Alkaloids Chemistry, Biological Significance, Applications and Ecological Role, 1st ed; Elsevier: The Netherlands, 2007.
[4]
Debnath, B.; Singh, W.S.; Das, M.; Goswami, S.; Singh, M.K.; Maiti, D.; Manna, K. Role of plant alkaloids on human health: A review of biological activities. Mater. Today Chem., 2018, 9, 56-72.
[http://dx.doi.org/10.1016/j.mtchem.2018.05.001]
[5]
Ziegler, J.; Facchini, P.J. Alkaloid biosynthesis: metabolism and trafficking. Annu. Rev. Plant Biol., 2008, 59(1), 735-769.
[http://dx.doi.org/10.1146/annurev.arplant.59.032607.092730] [PMID: 18251710]
[6]
Sandor, R.; Midlik, A.; Sebrlova, K.; Dovrtelova, G.; Noskova, K.; Jurica, J.; Slaninova, I.; Taborska, E.; Pes, O. Identification of metabolites of selected benzophenanthridine alkaloids and their toxicity evaluation. J. Pharm. Biomed. Anal., 2016, 121, 174-180.
[http://dx.doi.org/10.1016/j.jpba.2016.01.024] [PMID: 26808066]
[7]
Roy, A.A. Review on the alkaloids an important therapeutic compound from plants. IJPB, 2017, 1, 9.
[8]
Xi, X.; Gong, Y. Essentials of Chinese MateriaMedica and Medical Formulas, 1st ed; Elsevier: Netherlands, 2017.
[9]
Burnet, M.W.; Goldmann, A.; Message, B.; Drong, R.; El Amrani, A.; Loreau, O.; Slightom, J.; Tepfer, D. The stachydrine catabolism region in Sinorhizobium meliloti encodes a multi-enzyme complex similar to the xenobiotic degrading systems in other bacteria. Gene, 2000, 244(1-2), 151-161.
[http://dx.doi.org/10.1016/S0378-1119(99)00554-5] [PMID: 10689197]
[10]
Chen, H.X.; Shen, S.L.; Han, F.M.; Chen, Y. HPLC-ESI/MS analysis of stachydrine and its metabolites in rat urine. Yao Xue Xue Bao, 2006, 41(5), 467-470.
[PMID: 16848326]
[11]
Schmeller, T.; El-Shazly, A.; Wink, M. Allelochemical activities of pyrrolizidine alkaloids: interactions with neuroreceptors and acetylcholine related enzymes. J. Chem. Ecol., 1997, 23(2), 399-416.
[http://dx.doi.org/10.1023/B:JOEC.0000006367.51215.88]
[12]
Mattocks, A.R.; White, I.N.H. Estimation of metabolites of pyrrolizidine alkaloids in animal tissues. Anal. Biochem., 1970, 38(2), 529-535.
[http://dx.doi.org/10.1016/0003-2697(70)90478-1] [PMID: 5493074]
[13]
Shu, F.Z.; Xue, Q.Y.; Guangji, W.; Wang, G. Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update. Curr. Drug Metab., 2007, 8(6), 526-553.
[http://dx.doi.org/10.2174/138920007781368863] [PMID: 17691916]
[14]
Skoneczny, D.; Weston, P.; Zhu, X.; Gurr, G.; Callaway, R.; Weston, L. Metabolic profiling of pyrrolizidine alkaloids in foliage of two echium spp. invaders in Australia: A case of novel weapons? Int. J. Mol. Sci., 2015, 16(11), 26721-26737.
[http://dx.doi.org/10.3390/ijms161125979] [PMID: 26561809]
[15]
Euler, U.S.; Domeij, B. Nicotine-like actions of arecoline. Acta. Pharmacol. Toxicol., 1945, 1(3), 263-269.
[http://dx.doi.org/10.1111/j.1600-0773.1945.tb02581.x] [PMID: 21028316]
[16]
Chang, E.E.; Miao, Z.F.; Lee, W.J.; Chao, H.R.; Li, L.A.; Wang, Y.F.; Ko, Y.C.; Tsai, F.Y.; Yeh, S.C.; Tsou, T.C. Arecoline inhibits the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1A1 activation in human hepatoma cells. J. Hazard. Mater., 2007, 146(1-2), 356-361.
[http://dx.doi.org/10.1016/j.jhazmat.2006.12.035] [PMID: 17234337]
[17]
Garg, A.; Chaturvedi, P.; Gupta, P.C. A review of the systemic adverse effects of areca nut or betel nut. Indian J. Med. Paediatr. Oncol., 2014, 35(1), 3-9.
[http://dx.doi.org/10.4103/0971-5851.133702] [PMID: 25006276]
[18]
France, L. Betal-quid and areca-nut chewing and some areca nut derived nitrosamines; World Health Organization, 2004, pp. 160-167.
[19]
Giri, S.; Idle, J.R.; Chen, C.; Zabriskie, T.M.; Krausz, K.W.; Gonzalez, F.J. A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse. Chem. Res. Toxicol., 2006, 19(6), 818-827.
[http://dx.doi.org/10.1021/tx0600402] [PMID: 16780361]
[20]
Patel, K.; Patel, D.K. Medicinal significance, pharmacological activities, and analytical aspects of ricinine: A concise report. J. Coast. Life Med., 2016, 4(8), 663-667.
[http://dx.doi.org/10.12980/jclm.4.2016J6-96]
[21]
Leete, E. Biosynthesis of coniine from octanoic acid in hemlock plants (Conium maculatum). J. Am. Chem. Soc., 1970, 92(12), 3835.
[http://dx.doi.org/10.1021/ja00715a074] [PMID: 5422776]
[22]
Bevan, J.A. Action of lobeline and capsaicine on afferent endings in the pulmonary artery of the cat. Circ. Res., 1962, 10(5), 792-797.
[http://dx.doi.org/10.1161/01.RES.10.5.792] [PMID: 13868727]
[23]
Song, W.; Peng, Z.; Ge, B.; Han, F.; Chen, Y. Identification of metabolites of lobeline in the rat urine by liquid chromatography–tandem mass spectrometry. Int. J. Mass Spectrom., 2008, 269(1-2), 131-137.
[http://dx.doi.org/10.1016/j.ijms.2007.09.015]
[24]
Floris, G.; Mondovì, B. Copper Amine Oxidases: Structures, Catalytic Mechanisms and Role in Pathophysiology, 1st ed; CRC Press: United States, 2009.
[http://dx.doi.org/10.1201/9781420076813]
[25]
Seigler, D.S. Plant Secondary Metabolites; Springer: Germany, 1998.
[26]
Moncrieff, J. Simultaneous determination of sparteine and its 2-dehydro and 5-dehydro metabolites in urine by high-performance liquid chromatography with electrochemical detection. J. Chromatogr., Biomed. Appl., 1990, 529(1), 194-200.
[http://dx.doi.org/10.1016/S0378-4347(00)83822-0] [PMID: 2211932]
[27]
Ebner, T.; Meese, C.O.; Eichelbaum, M. Mechanism of cytochrome P450 2D6-catalyzed sparteine metabolism in humans. Mol. Pharmacol., 1995, 48(6), 1078-1086.
[PMID: 8848008]
[28]
Pharmacognosy. Strychnine-found in the seeds of Strychnos nux vomica., 2012. Available from: http://www.epharmacognosy.com/2012/07/strychnine-found-in-seeds-of-strychnos.html
[29]
Mishima, M.; Tanimoto, Y.; Oguri, Z.; Yoshimura, H. Metabolism of strychnine in vitro. Drug Metab. Dispos., 1985, 13(6), 716-721.
[PMID: 2867877]
[30]
Yin, W.; Wang, T.S.; Yin, F.Z.; Cai, B.C. Analgesic and anti-inflammatory properties of brucine and brucine N-oxide extracted from seeds of Strychnos nux vomica. J. Ethnopharmacol., 2003, 88(2-3), 205-214.
[http://dx.doi.org/10.1016/S0378-8741(03)00224-1] [PMID: 12963144]
[31]
Chen, X.; Lai, Y.; Cai, Z. Simultaneous analysis of strychnine and brucine and their major metabolites by liquid chromatography-electrospray ion trap mass spectrometry. J. Anal. Toxicol., 2012, 36(3), 171-176.
[http://dx.doi.org/10.1093/jat/bks004] [PMID: 22417832]
[32]
Tian, J.X.; Wang, M.; Xu, L.; Tian, Y.; Song, R.; Xu, F.G.; Zhang, Z.J. Metabolism of brucine: The important metabolic pathways of dihydroindole-type alkaloid for excretion in rats. Bioanalysis, 2014, 6(2), 137-149.
[http://dx.doi.org/10.4155/bio.13.290] [PMID: 24423592]
[33]
Malikova, J.; Zdarilova, A.; Hlobilkova, A. Effects of sanguinarine and chelerythrine on the cell cycle and apoptosis. In: Biomed. PapPalacky Univ. Olomouc; , 2006; 150, p. 5.
[34]
Dvorák, Z.; Simánek, V. Metabolism of sanguinarine: The facts and the myths. Curr. Drug Metab., 2007, 8(2), 173-176.
[http://dx.doi.org/10.2174/138920007779815959] [PMID: 17305495]
[35]
Zhang, H.H.; Wu, Y.; Sun, Z.L.; Liu, Z.Y. Identification of sanguinarine metabolites in pig liver preparations by accurate mass measurements using electrospray ionization hybrid ion trap/time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom., 2013, 27(9), 979-984.
[http://dx.doi.org/10.1002/rcm.6538] [PMID: 23592200]
[36]
Akinboye, E.S.; Bakare, O. Biological activities of emetine. Open Nat. Products J., 2011, 4, 8-15.
[http://dx.doi.org/10.2174/1874848101104010008]
[37]
Asano, T.; Kushida, H.; Sadakane, C.; Ishihara, K.; Wakui, Y.; Yanagisawa, T.; Kimura, M.; Kamei, H.; Yoshida, T. Metabolism of ipecac alkaloids cephaeline and emetine by human hepatic microsomal cytochrome P450s, and their inhibitory effects on P450 enzyme activities. Biol. Pharm. Bull., 2001, 24(6), 678-682.
[http://dx.doi.org/10.1248/bpb.24.678] [PMID: 11411558]
[38]
Asano, T.; Watanabe, J.; Sadakane, C.; Ishihara, K.; Hirakura, K.; Wakui, Y.; Yanagisawa, T.; Kimura, M.; Kamei, H.; Yoshida, T.; Fujii, Y.; Yamashita, M. Biotransformation of the ipecac alkaloids cephaeline and emetine from ipecac syrup in rats. Eur. J. Drug Metab. Pharmacokinet., 2002, 27(1), 29-35.
[http://dx.doi.org/10.1007/BF03190402] [PMID: 11996324]
[39]
Verheij, T.J.; Hopstaken, R.M.; Prins, J.M.; Salomé, P.L.; Bindels, P.J. Summary of NHG practice guideline ‘Acute cough’. Nederl. Tijdschr. Geneesk., 2011, 156, A4188.
[40]
Tsunoda, N.; Yoshimura, H. Metabolic fate of noscapine. II. Isolation and identification of novel metabolites produced by C-C bond cleavage. Xenobiotica, 1979, 9(3), 181-187.
[http://dx.doi.org/10.3109/00498257909038719] [PMID: 473793]
[41]
Liu, C.X.; Xiao, P.G.; Liu, G.S. Studies on plant resources, pharmacology and clinical treatment with berbamine. Phytother. Res., 1991, 5(5), 228-230.
[http://dx.doi.org/10.1002/ptr.2650050508]
[42]
Sun, Y.; Yao, T.; Li, H.; Peng, Y.; Zheng, J. In vitro and in vivo metabolic activation of berbamine to quinone methide intermediate. J. Biochem. Mol. Toxicol., 2017, 31(4), e21876.
[http://dx.doi.org/10.1002/jbt.21876] [PMID: 27902864]
[43]
Aceto, M.D.; Harris, L.S.; Abood, M.E.; Rice, K.C. Stereoselective μ- and δ-opioid receptor-related antinociception and binding with (+)-thebaine. Eur. J. Pharmacol., 1999, 365(2-3), 143-147.
[http://dx.doi.org/10.1016/S0014-2999(98)00862-0] [PMID: 9988096]
[44]
Misra, A.L.; Pontani, R.B.; Mulé, S.J. Pharmacokinetics and metabolism of (3H) thebaine. Xenobiotica, 1974, 4(1), 17-32.
[http://dx.doi.org/10.3109/00498257409052087] [PMID: 4826813]
[45]
Smith, H.S. Opioid metabolism. Mayo Clin. Proc., 2009, 84(7), 613-624.
[http://dx.doi.org/10.1016/S0025-6196(11)60750-7] [PMID: 19567715]
[46]
Kovacic, P.; Somanathan, R. Novel, unifying mechanism for mescaline in the central nervous system: Electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships. Oxid. Med. Cell. Longev., 2009, 2(4), 181-190.
[http://dx.doi.org/10.4161/oxim.2.4.9380] [PMID: 20716904]
[47]
Charalampous, K.D.; Walker, K.E.; Kinross-Wright, J. Metabolic fate of mescaline in man. Psychopharmacol., 1966, 9(1), 48-63.
[http://dx.doi.org/10.1007/BF00427703] [PMID: 5989103]
[48]
Britannica.. The Editors of Encyclopaedia. "bufotenine". Encyclopedia Britannica., 2021. Available from: https://www.britannica. com/science/bufotenine Accessed 10 January 2023.
[49]
Sanders, E.; Bush, M.T. Distribution, metabolism and excretion of bufotenine in the rat with preliminary studies of its O-methyl derivative. J. Pharmacol. Exp. Ther., 1967, 158(2), 340-352.
[PMID: 6065154]
[50]
Passie, T.; Seifert, J.; Schneider, U.; Emrich, H.M. The pharmacology of psilocybin. Addict. Biol., 2002, 7(4), 357-364.
[http://dx.doi.org/10.1080/1355621021000005937] [PMID: 14578010]
[51]
Schiff, P.L. Ergot and its alkaloids. Am. J. Pharm. Educ., 2006, 70(5), 98.
[http://dx.doi.org/10.5688/aj700598] [PMID: 17149427]
[52]
Passie, T.; Halpern, J.H.; Stichtenoth, D.O.; Emrich, H.M.; Hintzen, A. The pharmacology of lysergic acid diethylamide: A review. CNS Neurosci. Ther., 2008, 14(4), 295-314.
[http://dx.doi.org/10.1111/j.1755-5949.2008.00059.x] [PMID: 19040555]
[53]
Shamima, A.R.; Fakurazi, S.; Hidayat, M.T.; Hairuszah, I.; Moklas, M.A.M.; Arulselvan, P. Antinociceptive action of isolated mitragynine from Mitragyna speciosa through activation of opioid receptor system. Int. J. Mol. Sci., 2012, 13(9), 11427-11442.
[http://dx.doi.org/10.3390/ijms130911427] [PMID: 23109863]
[54]
Philipp, A.A.; Wissenbach, D.K.; Zoerntlein, S.W.; Klein, O.N.; Kanogsunthornrat, J.; Maurer, H.H. Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometry. J. Mass Spectrom., 2009, 44(8), 1249-1261.
[http://dx.doi.org/10.1002/jms.1607] [PMID: 19536806]
[55]
Kamble, S.H.; Sharma, A.; King, T.I.; León, F.; McCurdy, C.R.; Avery, B.A. Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom). Xenobiotica, 2019, 49(11), 1279-1288.
[56]
Nicola, C.; Salvador, M.; Escalona Gower, A.; Moura, S.; Echeverrigaray, S. Chemical constituents antioxidant and anticholinesterasic activity of Tabernaemontana catharinensis. Sci. World J., 2013, 2013, 519858.
[http://dx.doi.org/10.1155/2013/519858] [PMID: 23983637]
[57]
Alper, K.R. The Alkaloids: Chemistry and Biology; Elsevier: Amsterdam, 2001, 82, p. 38.
[58]
Mash, D.C.; Staley, J.K.; Baumann, M.H.; Rothman, R.B.; Lee Hearn, W. Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Life Sci., 1995, 57(3), PL45-PL50.
[http://dx.doi.org/10.1016/0024-3205(95)00273-9] [PMID: 7596224]
[59]
Gutser, U.T.; Friese, J.; Heubach, J.F.; Matthiesen, T.; Selve, N.; Wilffert, B.; Gleitz, J. Mode of antinociceptive and toxic action of alkaloids of Aconitum spec. Naunyn Schmiedebergs Arch. Pharmacol., 1997, 357(1), 39-48.
[http://dx.doi.org/10.1007/PL00005136] [PMID: 9459571]
[60]
Zhang, H.G.; Sun, Y.; Duan, M.Y.; Chen, Y.J.; Zhong, D.F.; Zhang, H.Q. Separation and identification of Aconitum alkaloids and their metabolites in human urine. Toxicon, 2005, 46(5), 500-506.
[http://dx.doi.org/10.1016/j.toxicon.2005.06.014] [PMID: 16135377]
[61]
Tang, L.; Ye, L.; Lv, C.; Zheng, Z.; Gong, Y.; Liu, Z. Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes. Toxicol. Lett., 2011, 202(1), 47-54.
[http://dx.doi.org/10.1016/j.toxlet.2011.01.019] [PMID: 21277363]
[62]
Pelletier, S.W. Alkaloids: Chemical and Biological Perspectives, 1st ed; Elsevier: The Netherlands, 1999.
[63]
Lyu, C.; Zhou, W.; Zhang, Y.; Zhang, S.; Kou, F.; Wei, H.; Zhang, N.; Zuo, Z. Identification and characterization of in vitro and in vivo metabolites of steroidal alkaloid veratramine. Biopharm. Drug Dispos., 2015, 36(5), 308-324.
[http://dx.doi.org/10.1002/bdd.1942] [PMID: 25765359]
[64]
Cermanova, J.; Kadova, Z.; Zagorova, M.; Hroch, M.; Tomsik, P.; Nachtigal, P.; Kudlackova, Z.; Pavek, P.; Dubecka, M.; Ceckova, M.; Staud, F.; Laho, T.; Micuda, S. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms. Toxicol. Appl. Pharmacol., 2015, 285(1), 12-22.
[http://dx.doi.org/10.1016/j.taap.2015.03.004] [PMID: 25771127]
[65]
Hroch, M.; Mičuda, S.; Cermanová, J.; Chládek, J.; Tomšík, P. Development of an HPLC fluorescence method for determination of boldine in plasma, bile and urine of rats and identification of its major metabolites by LC-MS/MS. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2013, 936, 48-56.
[http://dx.doi.org/10.1016/j.jchromb.2013.07.009] [PMID: 23973534]
[66]
Kubínová, R.; Machala, M.; Minksová, K.; Neca, J.; Suchý, V. Chemoprotective activity of boldine: Modulation of drug-metabolizing enzymes. Pharmazie, 2001, 56(3), 242-243.
[PMID: 11265593]

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