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Green tomatoes contain significant levels of steroidal glycoalkoids (SGA) such as α-tomatine and green pigment chlorophyll. Tomatine is an admixture of two glycoalkoids; alpha tomatine and dehydrotomatine reported various health beneficial biological activities. Moreover, a hydrolyzed product of tomatine also contributes to age-related atrophy, and muscle weakness and helps the elderly recover from illness and injuries related to age. However, there is a lack of evidence regarding the absorption of tomatine in the human body concerning proposed biological activity, which should be an area of interest in the future. Once, the absorption study is established compounds concentrated in green tomatoes are potentially involved as protective compounds for several diseases and also used for functional food. To facilitate the use of green tomatoes in food processing, this comprehensive review provides data on the nutritional value of green tomatoes, with emphasis on the evolution of the physiological chemistry, analytical, medicinal, and pharmacological effects of the α-tomatine and chlorophyll in an experimental model. The broad aim of this review is to evaluate the health benefits of green tomatoes in addition to their nutritional value and to study the several features of the role of α-tomatine and chlorophyll in human health.

The steroidal glycoalkaloid α-tomatine (αTM) and its aglycone tomatidine (TD) are abundant in the skin of unripe green tomato and present in tomato leaves and flowers. They mainly serve as defensive agents to protect the plant against infections by insects, bacteria, parasites, viruses, and fungi. In addition, the two products display a range of pharmacological properties potentially useful to treat various human diseases. We have analyzed all known pharmacological activities of αTM and TD, and the corresponding molecular targets and pathways impacted by these two steroidal alkaloids. In experimental models, αTM displays anticancer effects, particularly strong against androgen-independent prostate cancer, as well as robust antifungal effects. αTM is a potent cholesterol binder, useful as a vaccine adjuvant to improve delivery of protein antigens or therapeutic oligonucleotides. TD is a much less cytotoxic compound, able to restrict the spread of certain viruses (such as dengue, chikungunya and porcine epidemic diarrhea viruses) and to provide cardio and neuro-protective effects toward human cells. Both αTM and TD exhibit marked anti-inflammatory activities. They proceed through multiple signaling pathways and protein targets, including the sterol C24 methyltransferase Erg6 and vitamin D receptor, both directly targeted by TD. αTM is a powerful regulator of the NFkB/ERK signaling pathway implicated in various diseases. Collectively, the analysis shed light on the multitargeted action of αTM/TD and their usefulness as chemo-preventive or chemotherapeutic agents. A novel medicinal application for αTM is proposed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Stigmasterol, bergapten, and α-tomatine were isolated from tomato roots. The preliminary phytotoxic activities of stigmasterol and α-tomatine were evaluated in a wheat-coleoptile bioassay, and α-tomatine was more active than stigmasterol. To confirm its phytotoxic activity, α-tomatine was tested on Lactuca sativa and two weeds ( Lolium perenne and Echinochloa crus-galli), and it was active in all cases. The stimulatory activities of α-tomatine and stigmasterol on parasitic-plant germination were also evaluated, and α-tomatine was found to be active on Phelipanche ramosa, a parasitic plant of tomato. α-Tomatine was identified in root exudates by LC-MS/MS. This confirms that α-tomatine is exuded by roots into the environment, where it could act as both an allelochemical and a stimulator of P. ramosa, a parasitic plant of tomato.

The present study investigated the inhibitory effects of the commercial tetrasaccharide tomato glycoalkaloid tomatine and the aglycone tomatidine on three mucosal pathogenic protozoa that are reported to infect humans, cattle, and cats, respectively: Trichomonas vaginalis strain G3, Tritrichomonas foetus strain D1, and Tritrichomonas foetus strain C1. A preliminary screen showed that tomatine at 100 μM concentration completely inhibited the growth of all three trichomonads. In contrast, the inhibition of all three pathogens by tomatidine was much lower, suggesting the involvement of the lycotetraose carbohydrate side chain in the mechanism of inhibition. Midpoints of concentration-response sigmoid plots of tomatine on the three strains correspond to IC 50 values, the concentration that inhibits 50% of growth of the pathogenic protozoa. The concentration data were used to calculate the IC 50 values for G3, D1, and C1 of 7.9, 1.9, and 2.2 μM, respectively. The results show an approximately 4-fold variation from the lowest to the highest value (lowest activity). Although the inhibition by tomatine was not as effective as that of the medicinal drug metronidazole, the relatively low IC 50 values for both T. vaginalis and T. foetus indicated tomatine as a possible natural alternative therapeutic for trichomoniasis in humans and food-producing (cattle and pigs) and domestic (cats) animals. Because tomatine has the potential to serve as a new antiprotozoan functional (medical) food, the distribution of this glycoalkaloid in tomatoes and suggestions for further research are discussed.

Glycoalkaloids are secondary metabolites commonly found in Solanaceae plants. They have anti-bacterial, anti-fungal and insecticidal activities. In the present study we examine the effects of potato and tomato leaf extracts and their main components, the glycoalkaloids α-solanine, α-chaconine and α-tomatine, on development and reproduction of Drosophila melanogaster wild-type flies at different stages. Parental generation was exposed to five different concentrations of tested substances. The effects were examined also on the next, non-exposed generation. In the first (exposed) generation, addition of each extract reduced the number of organisms reaching the pupal and imaginal stages. Parent insects exposed to extracts and metabolites individually applied showed faster development. However, the effect was weaker in case of single metabolites than in case of exposure to extracts. An increase of developmental rate was also observed in the next, non-exposed generation. The imagoes of both generations exposed to extracts and pure metabolites showed some anomalies in body size and malformations, such as deformed wings and abdomens, smaller black abdominal zone. Our results further support the current idea that Solanaceae can be an impressive source of molecules, which could efficaciously be used in crop protection, as natural extract or in formulation of single pure metabolites in sustainable agriculture.

Inhibition of cancer can occur via apoptosis, a genetically directed process of cell self-destruction that involves numerous biomarkers and signaling pathways. Glycoalkaloids are nitrogen-containing secondary plant metabolites found in numerous Solanaceous plants including eggplants, potatoes, and tomatoes. Exposure of cancer cells to glycoalkaloids produced by eggplants (α-solamargine and α-solasonine), potatoes (α-chaconine and α-solanine), and tomatoes (α-tomatine) or their hydrolysis products (mono-, di-, and trisaccharide derivatives and the aglycones solasodine, solanidine, and tomatidine) inhibits the growth of the cells in culture (in vitro) as well as tumor growth in vivo. This overview comprehensively surveys and consolidates worldwide efforts to define the following aspects of these natural compounds: (a) their prevalence in the three foods; (b) their chemistry and structure-activity relationships; (c) the reported factors (biomarkers, signaling pathways) associated with apoptosis of bone, breast, cervical, colon, gastric, glioblastoma, leukemia, liver, lung, lymphoma, melanoma, pancreas, prostate, and squamous cell carcinoma cell lines in vitro and the in vivo inhibition of tumor formation and growth in fish and mice and in human skin cancers; and (d) future research needs. The described results may make it possible to better relate the structures of the active compounds to their health-promoting function, individually, in combination, and in food, and allow the consumer to select glycoalkaloid-containing food with the optimal content of nontoxic beneficial compounds. The described findings are expected to be a valuable record and resource for further investigation of the health benefits of food-related natural compounds.

Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Obesity is a risk factor for numerous metabolic disorders. Recently, natural compounds that may be beneficial for improving obesity have received increasing attention. In this study, we investigated whether red and green tomato extracts attenuate high-fat-diet-induced obesity in C57BL/6 mice. The mice were maintained on a normal diet (ND) or high-fat diet (HFD) for 4 weeks and then fed ND, HFD, HFD plus 2% red tomato extract (RTE) or HFD plus 2% green tomato extract (GTE) for 13 weeks. The weekly food intakes among the groups were not significantly different. Body weight of mice fed HFD plus GTE was significantly decreased to the level of mice fed ND, but the body weight was only slightly reduced in mice fed HFD plus RTE. Epididymal adipose tissue and liver weights were significantly decreased in mice fed HFD plus GTE compared to those in HFD. Serum total cholesterol and low-density lipoprotein cholesterol levels in mice fed GTE were modestly reduced, and liver total cholesterol level was strongly decreased in HFD plus GTE-fed mice compared to that in HFD-fed mice. Adenosine-monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase phosphorylation in liver from HFD plus GTE-fed mice was significantly elevated, and HMG-CoA reductase expression was also significantly decreased. GTE strongly decreased the expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha and perilipin in the adipose tissue of mice fed HFD plus GTE. Our results indicate that the antiobesity effects of GTE may be associated with activation of the AMPK pathway., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Steroidal alkaloids (SAs) are triterpene-derived specialized metabolites found in members of the Solanaceae family that provide plants with a chemical barrier against a broad range of pathogens. Their biosynthesis involves the action of glycosyltransferases to form steroidal glycoalkaloids (SGAs). To elucidate the metabolism of SGAs in the Solanaceae family, we examined the tomato (Solanum lycopersicum) GLYCOALKALOID METABOLISM1 (GAME1) gene. Our findings imply that GAME1 is a galactosyltransferase, largely performing glycosylation of the aglycone tomatidine, resulting in SGA production in green tissues. Downregulation of GAME1 resulted in an almost 50% reduction in α-tomatine levels (the major SGA in tomato) and a large increase in its precursors (i.e., tomatidenol and tomatidine). Surprisingly, GAME1-silenced plants displayed growth retardation and severe morphological phenotypes that we suggest occur as a result of altered membrane sterol levels caused by the accumulation of the aglycone tomatidine. Together, these findings highlight the role of GAME1 in the glycosylation of SAs and in reducing the toxicity of SA metabolites to the plant cell.

Tomato plants ( Lycopersicon esculentum ) synthesize the glycoalkaloids dehydrotomatine and alpha-tomatine, possibly as a defense against bacteria, fungi, viruses, and insects. Six green and three red tomato extracts were investigated for their ability to induce cell death in human cancer and normal cells using a microculture tetrazolium (MTT) assay. Compared to untreated controls, the high-tomatine green tomato extracts strongly inhibited the following human cancer cell lines: breast (MCF-7), colon (HT-29), gastric (AGS), and hepatoma (liver) (HepG2), as well as normal human liver cells (Chang). There was little inhibition of the cells by the three low-tomatine red tomato extracts. Cell death induced by the pure glycoalkaloids dehydrotomatine and alpha-tomatine isolated from green tomatoes and characterized by HPLC, GC, and GC-MS, as well as their respective aglycones tomatidenol and tomatidine, was also evaluated. alpha-Tomatine was highly effective in inhibiting all of the cell lines. Dehydrotomatine, tomatidenol, and tomatidine had little, if any, effect on cell inhibition. The results show that the susceptibility to destruction varies with the nature of the alkaloid and plant extract and the type of cancer cell. These findings extend related observations on the anticarcinogenic potential of glycoalkaloids and suggest that consumers may benefit by eating not only high-lycopene red tomatoes but also green tomatoes containing glycoalkaloids. Possible mechanisms of the anticarcinogenic and other beneficial effects and the significance of the cited observations for breeding improved tomatoes and for the human diet are discussed.

Culturable leaf-associated bacteria inhabiting a plant have been considered as promising biological control agent (BCA) candidates because they can survive on the plant. We investigated the relationship between bacterial groups of culturable leaf-associated bacteria on greenhouse- and field-grown tomato leaves and their antifungal activities against tomato diseases in vitro and in vivo. In addition, the isolated bacteria were analyzed for N-acyl-homoserine lactone (AHL) and indole-3-acetic acid (IAA) production, which have been reported to associate with bacterial colonization, and resistance to a tomato alkaloid (alpha-tomatine). Leaf washings and subsequent leaf macerates were used to estimate the population size of epiphytic and more internal bacteria. Bacterial population sizes on leaves at the same position increased as the leaves aged under both greenhouse and field conditions. Field-grown tomatoes had significantly larger population sizes than greenhouse-grown tomatoes. Analysis of 16S rRNA gene (rDNA) sequencing using 887 culturable leaf-associated bacteria revealed a predominance of the Bacillus and Pseudomonas culturable leaf-associated bacterial groups on greenhouse- and field-grown tomatoes, respectively. Curtobacterium and Sphingomonas were frequently recovered from both locations. From the 2138 bacterial strains tested, we selected several strains having in vitro antifungal activity against three fungal pathogens of tomato: Botrytis cinerea, Fulvia fulva, and Alternaria solani. Among bacterial strains with strong in vitro antifungal activities, Bacillus and Pantoea tended to show strong antifungal activities, whereas Curtobacterium and Sphingomonas were not effective. The results indicated the differences in antifungal activity among predominant bacterial groups. Analysis of alpha-tomatine resistance revealed that most bacterial strains in the dominant groups exhibited moderate or high resistance to alpha-tomatine in growth medium. Furthermore, some Sphingomonas and Pantoea strains showed AHL and IAA production activities. Strain 125NP12 (Pantoea ananatis) showed particular alpha-tomatine resistance, and AHL and IAA production had the highest protective value (91.7) against gray mold. Thus, the differences of these physiological properties among dominant bacteria may be associated with the disease suppression ability of BCAs on tomato plants.

Various physical and chemical properties of host plants influence insect larval performance and subsequent adult fitness. Tomato plants are relatively new hosts to the potato tuber moth, Phthorimaea operculella (Zeller), with the fruit being its preferred feeding site. However, it is unclear how the biochemical and physical properties of tomato fruits relate to potato tuber moth performance. Significant amounts of alpha-tomatine were detected in maturing green and ripening fruits of cherry (cv. Ceres) and processing (cv. Serio) types of tomatoes whereas none was detected in a fresh market variety (cv. Marglobe), at comparable stages. alpha-Tomatine is negatively and significantly correlated with development rate (head capsule size) of larvae reared in the fruits of the cherry and processing type tomatoes. Generally, survival, growth and development were significantly superior for larvae reared in the ripening fruits of the fresh market cultivar. At this stage, the fruits of this cultivar are also the largest. Based on these results it is concluded that fruit alpha-tomatine content, as well as fruit size and maturity, all affect performance of P. operculella larvae in the fruits of cultivated tomatoes.

Many fungal pathogens of tomato produce extracellular enzymes, collectively known as tomatinases, that detoxify the preformed antifungal steroidal glycoalkaloid alpha-tomatine. Tomatinase from the vascular wilt pathogen of tomato Fusarium oxysporum f. sp. lycopersici cleaves alpha-tomatine into the aglycon tomatidine (Td) and the tetrasaccharide lycotetraose (Lt). Although modes of action of alpha-tomatine have been extensively studied, those of Td and Lt are poorly understood. Here, we show that both Td and Lt inhibit the oxidative burst and hypersensitive cell death in suspension-cultured tomato cells. A tomatinase-negative F. oxysporum strain inherently non-pathogenic on tomato was able to infect tomato cuttings when either Td or Lt was present. These results suggest that tomatinase from F. oxysporum is required not only for detoxification of alpha-tomatine but also for suppression of induced defense responses of host.

Tomatoes, a major food source for humans, accumulate a variety of secondary metabolites including phenolic compounds, phytoalexins, protease inhibitors, and glycoalkaloids. These metabolites protect against adverse effects of hosts of predators including fungi, bacteria, viruses, and insects. Because glycoalkaloids are reported to be involved in host-plant resistance, on the one hand, and to have a variety of pharmacological and nutritional properties in animals and humans, on the other, a need exists to develop a better understanding of the role of these compounds both in the plant and in the diet. To contribute to this effort, this integrated review presents data on the history, composition, and nutrition of tomatoes, with special focus on the assessment of the chemistry, analysis, composition, nutrition, microbiology, and pharmacology of the tomato glycoalkaloids comprising alpha-tomatine and dehydrotomatine; their content in different parts of the tomato plant, in processed tomato products, and in wild and transgenic tomatoes; their biosynthesis, inheritance, metabolism, and catabolism; plant-microbe relationships with fungi, bacteria, viruses, insects, and worms; interactions with ergosterol and cholesterol; disruption of cell membranes; tomatine-induced tomatinases, pantothenate synthetase, steroid hydroxylases, and cytokines; and inhibition of acetylcholinesterase. Also covered are tomato-human pathogen relationships and tomatine-induced lowering of plasma cholesterol and triglycerides and enhancement of the immune system. Further research needs in each of these areas are suggested. The overlapping aspects are discussed in terms of general concepts for a better understanding of the impact of tomato glycoalkaloids in the plant in general and in food in particular. Such an understanding can lead to the creation of improved tomatoes and to improved practices on the farm and in the consumption of tomatoes.

The anti-fungal, steroidal, glycoalkaloid saponin, alpha-tomatine, is present in uninfected tomato plants in substantial concentrations, and may contribute to the protection of tomato plants against attack by phytopathogenic fungi. In general, successful fungal pathogens of tomato are more resistant to alpha-tomatine in vitro than fungi that do not infect this plant. For a number of tomato pathogens, this resistance has been associated with the ability to detoxify alpha-tomatine through the action of enzymes known as tomatinases. In contrast, the biotrophic tomato pathogen Cladosporium fulvum is sensitive to alpha-tomatine and is unable to detoxify this saponin. This paper describes the effects of heterologous expression of the cDNA encoding tomatinase from the necrotroph Septoria lycopersici in two different physiological races of C. fulvum. Tomatinase-producing C. fulvum transformants showed increased sporulation on cotyledons of susceptible tomato lines. They also caused more extensive infection of seedlings of resistant tomato lines. Thus, alpha-tomatine may contribute to the ability of tomato to restrict the growth of C. fulvum in both compatible and incompatible interactions.

Pretreatment of tomato seeds with pendimethalin or metribuzin and inoculation of seedlings with the antagonistic Streptomyces corchorusii or/and Streptomyces mutabilis were tested for the formation of tomatine in roots and stems of tomato, infested with Pseudomonas solancearum or/and Fusarium oxysporum f. sp. lycopersici. All treatments induced the formation of variable quantities of tomatine, compared with untreated control. The variation was proportional to: the pathogen, Fusarium was more stimulating than Pseudomonas; the antagonistic organism, S. corchorusii being more eliciting than S. mutabilis; the herbicide and its concentration, pendimethalin at 2 x 10(-3) M being the most eliciting of tomatine; and according to the soil, plants grown in non-sterilized soil accumulated more tomatine than did these grown in sterilized soil. In all treatments, stems had more tomatine than roots and non-sterilized soil was better than sterilized soil. The antagonistic streptomycetes induced accumulation of tomatine more than did the herbicides. The highest amounts of tomatine were detected in plants pretreated with pendimethalin at 2 x 10(-3) M, grown in non-sterilized soil, infested with F. oxysporum, and inoculated with S. corchorusii and S. mutabilis. The effect of the extracted tomatine on the growth of Fusarium and Pseudomonas was examined in vitro. The crude extract of tomatine from all treatments reduced growth and sporulation of F. oxysporum and growth of P. solanacearum in defined media. The reduction varied according to the treatment and was proportional to the quantities of extracted tomatine, the highest amounts being the most effective. The mechanism of phytoalexins in controlling tomato wilt pathogens was also discussed.