Tomatine

Not to be confused with Tomatin or thaumatin.
α-Tomatine
Names
IUPAC name
(22S,25S)-5α-spirosolan-3β-yl β-D-glucopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside [1]
Other names
Tomatine, Tomatin, Lycopersicin
Identifiers
17406-45-0 N
ChEBI CHEBI:9630 YesY
ChEMBL ChEMBL525778 YesY
ChemSpider 26536 YesY
Jmol interactive 3D Image
PubChem 623058
Properties
C50H83NO21 [2]
Molar mass 1034.18816 [3]
Appearance crystalline solid
Melting point 263-268 °C [4]
insoluble but soluble in methanol, ethanol, dioxane and propylene glycol[5]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Tomatine is a glycoalkaloid found in the stems and leaves of tomato plants, which has fungicidal properties.[6] Chemically pure tomatine is a white crystalline solid at standard temperature and pressure.[7][8] Tomatine as well as the a-glycone derivative Tomatidine have been shown to have multiple health benefits.[9] Dietary supplementation with ∼0.04% tomatidine for 10 weeks reduces plasma cholesterol and atherosclerosis in ApoE-deficient mice without evidence of toxicity[10] Moreover, tomatidine is a natural small molecule inhibitor of skeletal muscle atrophy and potential therapeutic agent for aging-associated sarcopenia reducing weakness and atrophy in aged skeletal muscle.[11][12] Tomatine has antimicrobial properties against certain classes of microbes although some microbes produce an enzyme called tomatinase which can degrade tomatine, rendering it ineffective as an antimicrobial.[13]

History

Tomatoes were brought to Europe in the 1590s. The English botanist John Gerard was one of the first cultivators of the tomato plant. In his publication Grete Herball he considered tomatoes as poisonous due to their levels of tomatine and high acid content. Consequently, tomatoes were not eaten until the mid-18th century.[14]

In 1837, the first medicinal tomato pills were advertised in the United States because of their positive effects upon the biliary organs. The product “Phelp’s Compound Tomato Pills” was extracted from the tomato plant and contained tomatine. The pills were made by the medic Guy R. Phelps who stated that the alkaloid tomatine was one of the most useful discoveries ever made. Tomatine then was said to be an antidote to mercury.[15]

In the mid 20th century, scientists from the U.S. Department of Agriculture were the first who isolated tomatine from the wild tomato species Lycopersicon pimpinelifolium and the cultured species Lycopersicon esculentum.[16][17] Since then, more research about tomatine is done.

Biosynthesis

α-Tomatine belongs to the compound group steroidal glycoalkaloids. These compounds consist of an aglycone, which is a cholesterol derivative, and a carbohydrate chain, which in the case of alpha-tomatine consists of two D-glucose units, a D-galactose unit and a D-xylose unit.[18] In α-tomatine the tetrasaccharide called lycotetraose is attached to the O-3 of the sterioidal aglycone.[19] At first it was thought that the synthesis of steroidal alkaloids only involved multiple steps of hydroxylation, oxidation and amination of cholesterol with arginine as the source of the incorporated nitrogen. Later the glycoalkaloid metabolism genes were discovered.[18] These genes produce the glycoalkaloid metabolism enzymes (GAME), which are responsible for the synthesis of steroidal alkaloid aglycones in potato and tomato plants.[18] The reaction these enzymes perform are shown in the figure 1.

Figure 1: Biosynthesis of α-tomatine (26) and other steroidal glycoalkaloids in Solanaceae species.[20]
Figuur 2: Mechanism of membrane disruption by glycoalkaloids [21]

Mechanism of action

The mechanism of action of the glycoalkaloids (to which tomatine belongs), can be divided in two main parts: the disruption of the membranes and the inhibition of acetylcholinesterase. Tomatine is responsible in tomato plants for resistance against for example the Colorado beetle and to snails.[22] It is also a defense against fungi.[23][24]

Membrane disruption

The membrane disruptive properties of tomatine are caused by the ability to form 1:1 complexes with cholesterol. A possible mechanism of the membrane disruption by glycoalkaloids is displayed in figure 2. First, the aglycon part of tomatine binds reversible to sterols in the membrane (figure 2, part 2). When this reaches a certain density, the glycosidic residues of the glycoalkaloids interact with eachother by electrostatic interactions. This interactions catalyze the development of an irreversible matrix of glycoalkaloid-sterol complexes (figure 2, part 4). In this way, the sterols from the external membrane are immobilized and membrane budding will arise. Tubular structures are formed, because of the structure of tomatine (figure 2, part 6). [22][25] This membrane disruption causes cell death by the leakage of the cell.[22] Also has the disrupted membrane an influence on the sodium transport. It alters the membrane potential and reduces the active sodium transport. When tomatine is orally taken, the brush border of the intestine is damaged by the membrane disruptive properties of tomatine, so increased uptake of macromolecules appears. This damage of the epithelial barriers is dose-dependent.[22][25] Research on fungi has proven that tomatine is only effective against fungi at pH 8 and not at pH 4. A possible explanation for this is that the tomatine only in the deprotonated form binds to cholesterol to form the earlier mentioned complexes.[23] Other research has proven that tomatine disrupt liposome membranes containing 3-ß-hydroxy sterol while liposomes without 3-ß-hydroxy sterols are resistant against membrane disruption.[24] Although, tomatine inhibits also the fungi types Ph. Infestans and Py. Aphanidermatum which do not have any sterols in their membranes, so another mechanism of action must be present.[23]

Inhibition of acetylcholinesterase

The other known mechanism of action is the pH-dependent competitive inhibition of acetylcholinesterase.[22][23] Acetylcholine plays a role in the transmission of signals from neurons to muscles. It is released from the neuron and by binding to the muscular membrane depolarization occurs. To have the possibility for receiving a new signal, the released acetylcholine should be broken down. The break down is usually done by acetylcholinesterase.[26] By inhibiting acetylcholinesterase, the released acetylcholine cannot be broken down and stays in the neuromuscular junction and in the synapses in the central nervous system. Also inhibition of butyrylcholinesterase can take place, which is reversible.[22] The function of butyrylcholineesterase is not fully understood, but it probably plays a role in cell growth.[26] The most synthetic pesticides used in the agriculture work by the inhibition of acetylcholinesterase, because of the ability to kill insects.[27]

Other mechanisms

There is a third mechanism by which tomatine can work in organisms. In a research by frogs, oral administration of low concentration tomatine has a cation effect on cardiac contractions. It is possible that the increased heart rate comes from alteration of the electric properties of heart cell membranes by positively charged tomatine ions because of participation in acid-base equilibriums.[23]

Tomatine can also stimulate the immune system by participation in a sequence of the respiratory burst. This provides cellular release of hydrogen peroxide, which is a immune modulator.[23] The respiratory burst uses hydrogen peroxide to form hypochlorite, which destroys bacteria.

The mechanism of action against cancer cells is not fully understood. It may be a result of the different earlier mentioned molecular interactions, as complexing with cholesterol, potentiation of the immune system and direct distruction by disruption of the cell membranes. In the case of cancer, also inhibition of invasion and migration is found. The mechanism for this is maybe through inactivation of PI3K/Akt of ERK signaling pathways, which inhibits transcriptional factors and DNA binding activities. This inhibition leads to decrease in MMP-2, MMP-9 and u-PA.[22] MMP-2, MMP-9 and u-PA are factors which are important in the metastasis of the cancer, by inhibiting this factors, the ability of the cancer to spread around the body is reduced.[28]

Metabolism

Until today, little is known about the bioavailability, pharmacokinetics and metabolism of the glycoalkaloids in human.[22] A fact is the bad uptake of tomatine into the general circulation. When tomatine is orally taken, the tomatine is going to form complexes with the cholesterol from the food present in the stomach. The complex of tomatine and cholesterol is not taken up in the intestine, but is excreted.[23] For the complexation with cholesterol the presence carbohydrate chain is essential. The aglycon tomatidine, which is tomatine without the sugars, does not form the complexes.[22][25] The complexation probably occurs in the duodenum, because the acidic conditions in the stomach leads to protonation of the tomatine. The protonated form of tomatine does not bind to cholesterol.[23]

It is likely that hydrolysis of tomatine takes place, but it is not known if it is acid or glycosidase catalyzed.[23] In vitro exposure of tomatine to 1 M HCl for 3 h by 37 degrees did not hydrolyse tomatine, so probably the tomatine is also not hydrolyzed by acid in the digestive tract of humans.[26] The hydroxylation of tomatine likely leads to the formation of tomatidine, which is the aglycon of tomatine. Tomatidine is a metabolite which is probably not completely non-toxic, it could have effect on the human body.[23]

Fungal tomatinases transform tomatine to deactive species. Detoxification can take place by removing one glucose residue. Other fungi species hydrolyzes tomatine to the less toxic aglycon tomatidine by removing all the sugar residues. Tomatidine can still inhibit some fungi species, but is less toxic than tomatine. The way of hydrolyzing of tomatine is different for different types of fungi. Also, the level of toxicity depends on the type of fungus.[24][29] The metabolite tomatidine can be hydrolysed further by membrane bound CYP-450 oxygenases.[23]

Uses

Tomatine has been used as a reagent in analytical chemistry for precipitating cholesterol from solution.[6][30] Also, tomatine is known to be an immune adjuvant in connection with certain protein antigens.[31]

Efficacy

Tomatine may play a major role in disease resistance in the tomato plant. Studies showed that the molecule possesses antibiotic properties against the human pathogens E.coli and Staphylococcus aureus and a variety of fungi.[23][32][33][34] [35] The presence of sterols in cell membranes of fungi and other pathogens makes it possible for glycoalkaloids to form complexes with sterols. Such binding results in the disruption of cell membranes, leakage of cell components and finally cell death.[36]

In vitro studies showed that tomatine increased the permeability of the small intestinal mucosal cell. Resulting in inhibition of active nutrient transport and facilitation of the uptake of gut contents that normally would not be taken.[23][37]

Side effects

Oral administration of tomatine to frogs induces a cation effect on cardiac contraction, producing symptoms of tachycardia.[23][38]

Injection of tomatine into mice caused a rapid drop in blood pressure. This is presumably the result of tomatine-induced disruption of red blood cell membranes. (Cholesterol seems to protect the erythrocytes.[39][40] Intraperitoneal injection of tomatine results in a decrease of dieresis in rats. This effect is accompanied by increased corticosteroid and neutrophil levels and a decrease in the Na/K ration in the serum.[23] The oral administration of tomatine in doses of 15-30 mg/kg or the intramuscular admistration in the dose range of 1-10 mg/kg  induces a dose-dependent inhibition of induced edema[23] similar anti-inflammatory effects are noted when tomatine is administered subcutaneously.

The human consumption of tomatine seems to go without apparent toxic effects.  This is reinforced by the widespread consumption of “pickled green” and “fried green tomatoes”  and the consumption of  high-tomatine tomatoes (a variant of L. esculentum var. cerasiforme indigenous to Peru) with  very high tomatine content (in the range of  500-5000 mg/kg of dry weight.[41]

Toxicity

The possible risks of tomatine on humans have not been studied, so no NOAEL can be deduced. The toxicity of tomatine has only been studied on laboratory animals. The symptoms of tomatine poisoning in animals are similar to the symptoms of poisoning by solanine, a potato glycoalkaloid. These sympotoms include vomiting, diarrhoea, abdominal pain, drowsiness, confusion, weakness and depression.[42] Generally, tomatine is regarded to cause less toxic effects to mammals than other alkaloids as solanine.[43] The amount of tomatine absorbed by the human body as well as the possible metabolism is unknown. There is no evidence that consumption of tomatoes causes acute toxic or genotoxic effects.[26]

Tomatine is considered to be a fungitoxic compound as it completely inhibits mycelial growth of the fungi C. orbiculare (MC100=2.0 mM), S. linicola (MC100=0.4 mM) and H. turcicum (MC100=0.13 mM). For the inhibition at a low pH, much more tomatine is required, so the compound is more fungitoxic at a high pH, when the alkaloid is unprotonated. The unprotonated form of tomatine forms complexes with sterols such as cholesterol which may cause disruption of cell membrane and changes in membrane permeability.[44]

Effects on animals

According to in vivo studies with mice, rats and hamsters, tomatine seems to be non-toxic when orally consumed (LD50=500 mg/kg).[45] Complex formation may be the reason why tomatine has a much lower oral toxicity than other glycoalkaloids.  Due to formation of insoluble complexes with sterols, tomatine is eliminated in the feces and only small amounts of tomatine are absorbed by the digestive tract.[46][47] The amount of plasma LDL cholesterol (low-density lipoprotein) decreases as the amount of dietary tomatine increases.[48] The LD50 value of tomatine when served intravenous is determined to be 18 mg/kg body weight.[47] When administered intraperiotoneal, the LD50 value is equal to 25 mg/kg body weight.[45] Generally, tomatine is less toxic than potato glycoalkaloids.

The influence of tomatine on rat hearts has been studied by adding the compound to a culture medium of neonatal rat cells. At a concentration of 20 µg/ml tomatine the contraction frequency increased within two hours. At a concentration of 40 µg/ml tomatine the heart cells stopped beating for some minutes.[49]

The effects of tomatine on frog embryos and frog skin were tested by fluorescence measurements. The membrane permeability of frog embryos increased by 600% when exposed with tomatine. In frog skin, the sodium-active transport decreased by 16%, which may lead to disruption of cell membranes.[50]

Injection of tomatine into mice also causes an increase in blood pressure due to hemolysis and calcium release from bone tissue. When administered intramusculary or orally to rats, tomatine inhibits induced edema.[23]

References

  1. ↑ http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9630
  2. ↑ 1.http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+17406-45-0
  3. ↑ U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file., p. 83/8212
  4. ↑ The Merck Index. 9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 1228
  5. ↑ The Merck Index. 9th ed. Rahway, New Jersey: Merck & Co., Inc., 1976., p. 1228
  6. 1 2 "tomatine." McGraw-Hill Dictionary of Scientific and Technical Terms. McGraw-Hill Companies, Inc., 2003. Answers.com 28 Mar. 2010. http://www.answers.com/topic/tomatine
  7. ↑ tomatine (CHEBI:9630)
  8. ↑ Degtyarenko, K.; De Matos, P.; Ennis, M.; Hastings, J.; Zbinden, M.; McNaught, A.; Alcantara, R.; Darsow, M.; Guedj, M.; Ashburner, M. (2007). "ChEBI: A database and ontology for chemical entities of biological interest". Nucleic Acids Research 36 (Database issue): D344–50. doi:10.1093/nar/gkm791. PMC 2238832. PMID 17932057.
  9. ↑ Friedman, Mendel (2013). "Anticarcinogenic, Cardioprotective, and Other Health Benefits of Tomato Compounds Lycopene, α-Tomatine, and Tomatidine in Pure Form and in Fresh and Processed Tomatoes". Journal of Agricultural and Food Chemistry 61 (40): 9534–50. doi:10.1021/jf402654e. PMID 24079774.
  10. ↑ Fujiwara, Y., Kiyota, N., Tsurushima, K., Yoshitomi, M., Horlad, H., Ikeda, T., ... & Nagai, R. (2012). Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA: cholesterol acyl-transferase (ACAT). Journal of agricultural and food chemistry, 60(10), 2472-2479. PubMed
  11. ↑ Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., ... & Adams, C. M. (2014). Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. Journal of Biological Chemistry, 289(21), 14913-14924. PMC 4031541
  12. ↑ Ebert, S. M., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., Murry, D. J., Fox, D. K., ... & Adams, C. M. (2015). Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Journal of Biological Chemistry, 290(42), 25497-25511. PMC 4646196
  13. ↑ Seipke, Ryan F.; Loria, Rosemary (2008). "Streptomyces scabies 87-22 Possesses a Functional Tomatinase". Journal of Bacteriology 190 (23): 7684–92. doi:10.1128/JB.01010-08. PMC 2583622. PMID 18835993.
  14. ↑
  15. ↑ Andrew F. Smith; The tomato in America: Early History, Culture, and Cookery; University of South Carolina Press, 1994; 112. 
  16. ↑ Fontaine, T. D.; Irving, G. W., Jr.; Ma, R.; Poole, J. B.; Doolittle, S. P; Isolation and partial characterization of crystalline tomatine, an antibiotic agent from the tomato plant; Arch. Biochem. 1948; 18, 467-475.
  17. ↑ Fontaine, T. D., Ard, J. S., Ma, R. M.; Tomatidine, a steroid secondary amine; J. Am. Chem. SOC, 1951; 73, 878-879.
  18. 1 2 3 P.D. Cárdenas, P.D. Sonawane, U. Heinig, S.E. Bocobza, S. Burdman, A. Aharoni; The bitter side of the nightshades: Genomics drives discovery in Solanaceae steroidal alkaloid metabolism
  19. ↑ Nigel A. Jones, Sergey A. Nepogodiev and Robert A. Field; Efficient synthesis of methyl lycotetraoside, the tetrasaccharide constituent of the tomato defence glycoalkaloid α-tomatine. 
  20. ↑ P.D. Cárdenas, P.D. Sonawane, U. Heinig, S.E. Bocobza, S. Burdman, A. Aharoni; The bitter side of the nightshades: Genomics drives discovery in Solanaceae steroidal alkaloid metabolism; 
  21. ↑ P.D. Cárdenas, P.D. Sonawane, U. Heinig, S.E. Bocobza, S. Burdman, A. Aharoni; The bitter side of the nightshades: Genomics drives discovery in Solanaceae steroidal alkaloid metabolism; 
  22. 1 2 3 4 5 6 7 8 9 Milner, Sinead Eileen, et al. "Bioactivities of glycoalkaloids and their aglycones from Solanum species." Journal of agricultural and food chemistry 59.8 (2011): 3454-3484.
  23. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Friedman, Mendel; Tomato glycoalkaloids: role in the plant and in the diet; Journal of Agricultural and Food Chemistry 50.21, 2002; 5751-5780.
  24. 1 2 3 Hoagland, Robert E.; Toxicity of tomatine and tomatidine on weeds, crops and phytopathogenetic fungi.; Allelopathy J 23.2, 2009; 425-436.
  25. 1 2 3 Keukens, Erik AJ, et al; Dual specificity of sterol-mediated glycoalkaloid induced membrane disruption; Biochimica et Biophysica Acta (BBA)-Biomembranes 1110.2, 1992; 127-136.
  26. 1 2 3 4 Andersson, Christer.; Glycoalkaloids in tomatoes, eggplants, pepper and two Solanum species growing wild in the Nordic countries.; Nordic Council of Ministers, 1999.
  27. ↑ Bushway, Rodney J., Sharon A. Savage, and Bruce S. Ferguson; Inhibition of acetyl cholinesterase by solanaceous glycoalkaloids and alkaloids; American potato journal 64.8, 1987; 
  28. ↑ Mook, Olaf RF, Wilma M. Frederiks, and Cornelis JF Van Noorden.; The role of gelatinases in colorectal cancer progression and metastasis.; Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1705.2, 2004; 69-89.
  29. ↑ Arneson, P. A., and R. D. Durbin.; Studies on the mode of action of tomatine as a fungitoxic agent.; Plant physiology 43.5, 1968; 683-686.
  30. ↑ Cayen, M. N. (1971). "Effect of dietary tomatine on cholesterol metabolism in the rat". Journal of Lipid Research 12 (4): 482–90. PMID 4362143.
  31. ↑ Heal, K. G.; Taylor-Robinson, A. W. (2010). "Tomatine Adjuvantation of Protective Immunity to a Major Pre-erythrocytic Vaccine Candidate of Malaria is Mediated via CD8+ T Cell Release of IFN-γ". Journal of Biomedicine and Biotechnology 2010: 834326. doi:10.1155/2010/834326. PMC 2837906. PMID 20300588.
  32. ↑ Fontaine, T. D., Irving, G. W., Jr., Ma, R. M., Poole, J. B., Doolittle, S. P.; Isolation and partial characterization of crystalline tomatine, an antibiotic agent form the tomato plant; Arch. Biochem., 1948; 18, 467-475.
  33. ↑ Kuhn, R., Lo ¨w, I., Trischmann, H.; The constitution of lycotetraose; Chem. Ber., 1957; 90, 208-213.
  34. ↑ Kuhn, R., Lo ¨w, I., Trischmann, H; The constitution of tomatine; Angew. Chem., 1956; 68, 212.
  35. ↑ Irving, G. W., Jr., The significance of tomatine in plant and animal disease; J. Wash. Acad. Sci., 1947; 37, 467-475.
  36. ↑ Blankemeyer, J. T., McWilliams, M. L., Rayburn, J. R., Weissenberg, M., Friedman, M.; Developmental toxicology of solamargine and solasonine glycoalkaloids in frog embryos; Food Chem. Toxicol., 1998; 36, 383-389.
  37. ↑ Johnson, I. T., Gee, J. M., Price, K., Curl, C., Fenwick, G. R.; Influence of saponins on gut permeability and active nutrient transport in vitro; J. Nutr., 1986; 116, 2270-2277.
  38. ↑ Nishie, K., Fitzpatrick, T. J., Swain, A. P., Keyl, A. C.; Positive inotropic action of Solanaceae glycoalkaloids; Res. Commun. Chem. Pathol. Pharmacol., 1976; 15, 601-607.
  39. ↑ Schloesser, E.; Role of saponins in antifungal resistance. IV. Tomatine-dependent development of fruit rot orgnism of tomato fruits.; Acta Phytopathol., 1975; 10, 77-87.
  40. ↑ Elferink, J. G. R.; The hemolytic action of saponins.; Pharm. Weekbl., 1977; 112, 1-10.
  41. ↑ Rick, C. M., Uhlig, J. W., Jones, A. D.; High R-tomatine content in ripe fruit of Andean Lycopersicon esculentum Var. cerasiforme: developmental and genetic aspects.; Proc. Natl. Acad. Sci. U.S.A., 1994; 91, 12877-12881.
  42. ↑ Morris, S.C., Lee, T.H; The toxicity and teratogenicity of Solanaceae glycoalkaloids, particularly those of the potato (Solanum tuberosum): a review.; Food Techn. Aust., 1984; 118-124.
  43. ↑ Rick, Charles M., John W. Uhlig, and A. Daniel Jones. "High alpha-tomatine content in ripe fruit of Andean Lycopersicon esculentum var. cerasiforme: developmental and genetic aspects." Proceedings of the National Academy of Sciences 91.26 (1994): 12877-12881.
  44. ↑ Arneson, P.A., Durbin, R.D.; Studies on the Mode of Action of Tomatine as a Fungitoxic Agent.; U.S.D.A. Pioneering Research Laboratory, 1967.
  45. 1 2 Sackmann, W.; Kern, H., Wiesmann, E.; Studies on the biological effects of solanine and tomatine.; Schweiz. Z. Allg. Pathol. Bakteriol., 1959; 22, 557-563.
  46. ↑ Cayen, M.N.; Effect of dietary tomatine on cholesterol metabolism in the rat; Journal of Lipid Research, Volume 12, 1971.
  47. 1 2 Wilson R. H., Poley G. W. and DeEds F.; Some pharmacologic and toxicologic properties of tomatine and its derivatives.; Toxicology and Applied Pharmacology 3, 1961; 39-48.
  48. ↑ Friedman, M., Fitch, T.E., Yokoyama, W.E.; Lowering of plasma LDL cholesterol in hamsters by the tomato glycoalkaloid tomatine; Division of Agricultural and Food Chemistry, 1997.
  49. ↑ Bergers, W.A., Alink, G.M.; Toxic effect of the glycoalkaloids solanine and tomatine on cultured neonatal rat heart cells; Toxicology Letters, 1980; 6, 29-32.
  50. ↑ Blankemeyer, J.T., White, J.B., Stringer, Friedman, M.; Effect of α-tomatine and tomatidine on membrane potentail of frog embryos and active transport of ions in frog skin.; Food and Chemical Toxicology, 1997; 35, 639-646.
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