Trigonelline is a bioactive pyridine alkaloid that occurs naturally in high concentrations in coffee (up to 7.2 g/kg) and coffee by-products (up to 62.6 g/kg) such as coffee leaves, flowers, cherry husks or pulp, parchment, silver skin, and spent grounds. In the past, coffee by-products were mostly considered waste and discarded. However, the use of coffee by-products as food has attracted interest because of their economic and nutritional value and the environmental benefits of sustainable resource use. Their authorization as so-called novel foods in the European Union may lead to increased oral exposure of the general population to trigonelline.
Trigonelline, as a constituent of green coffee beans, decomposes readily when heated at roasting temperatures above 180 °C [14], giving rise to various volatile derivatives such as pyrroles, alkylpyridines, and phenolic compounds, thereby influencing the flavor and aroma of coffee products. Additionally, nicotinic acid is produced as one of two non-volatile derivatives following N-demethylation (the second being N-methylpyridinium as a decarboxylation product) [17][55][74]. Serving as a precursor for essential nicotinic acid (niacin or vitamin B3) in coffee beans, trigonelline thus has nutritional value [8][17][74]. However, it is unclear whether intact trigonelline ingested via foods is metabolized to nicotinic acid in the human body and thus acts as a provitamin. Metabolic transformation to nicotinic acid is only assumed to potentially occur [26].
Trigonelline did not exert any cytotoxic effects in concentrations up to 100 µmol/L in human neuroblastoma SK-N-SH cells [75], human hepatocellular carcinoma (Hep3B) cells [76], human immortalized dermal keratinocytes (HaCat) and human foreskin fibroblasts (Hs68) [77] after treatment for six days, 48 and 24 h, respectively. In fact, in a recent study, trigonelline protected UV-B radiation-exposed Hs68 cells against photodamage by restoring the physiological function of the endoplasmic reticulum, decreasing oxidative stress, and positively modulating calcium homeostasis and apoptosis in a dose-responsive manner (10, 25, 50, and 100 µmol/L) [77]. It also did not alter the morphology of Madin–Darby bovine kidney cells and African green monkey kidney cells (Vero cells) at concentrations of 1.6 µg/mL each after 48 h of exposure [78].
Three animal studies were identified with designs appropriate for the investigation of subchronic toxicity. In cats (strain and sex not provided), trigonelline administered at doses up to 3500 mg/kg bw for 62–70 days did not induce any visible effects [79]. Additionally, when albino Sabra rats were fed 50 mg/kg bw of trigonelline daily for 21 days and sacrificed after 42 days, no changes in the weight of the thyroid, thymus, kidneys, liver, adrenals, ovaries, and uterus were observed [80].
The first in vitro experiments on the potential mutagenicity of trigonelline were conducted by Fung et al. in 1988. The scholars showed that pure trigonelline did not produce any mutagenic activity in an L5178Y TK+/− mouse lymphoma assay and several Salmonella typhimurium test systems (i.e., Ames tests) [10]. Contrarily, in the S. typhimurium assays conducted by Wu and colleagues, heated trigonelline, applied to the plates (a) alone and (b) combined with certain amino acids caused substantial amounts of revertants, especially when in binary combination with serine (12,740 revertants/mmol) or threonine (11,270/mmol). Of all the 13 single compounds examined in that study in strain TA98, heated trigonelline applied to the plates alone produced the most revertants (8160/mmol) and exhibited the highest mutagenicity [7].
Trigonelline has been examined for its potential role in cancer in several in vitro experiments. In only one study was it shown to have effects that could increase the risk of tumor formation, as it significantly induced the proliferation of MCF-7 breast cancer cells in a dose-responsive manner. Noticeably increased total cell numbers were observed at considerably low concentrations of 10 pmol/L, with the most potent proliferative effect yielded at 100 pmol/L. The growth-promoting effect was due to trigonelline binding the estrogen receptors (ER) of the MCF-7 cells in a way similar to estradiol, thereby altering ER-mediated transcription. As discussed by the scholars, trigonelline has no structural similarity to estradiol or phytoestrogens. Thus, the scholars suggested that trigonelline did not bind the active ligand binding site of the ER, but probably another domain, changing the receptors’ conformation and enabling binding of unspecified transcriptional co-regulators. Hence, trigonelline exerted sound estrogenic activity [81]. This is a significant finding as increased estrogenic activity—either induced by pathological overexpression of ER or mediated by estrogen-like compounds encountered, for instance, via the diet—has been shown to be an important factor in some types of cancer (e.g., breast, colorectal, endometrial, and ovarian cancer [82]), as it stimulates cell growth and proliferation, promoting cancer initiation [83].
Except for one in vivo study from 2009, no data on reproductive toxicity or teratogenic effects are available. In that study, Aswar et al. aimed to investigate the effects of trigonelline on the estrous cycle and fertility of female Wistar rats. To examine effects on the estrous cycle (endpoint: vaginal cornification), the scholars administered doses of 75 mg/kg bw of trigonelline orally to ovariectomized, immature female Wister rats weighing 55–60 g twice on the first two days and once on the third and fourth day of the treatment. Afterwards, vaginal smears were collected and microscopically searched for cornified or nucleated epithelial cells. As no such cells were noticed, it was concluded that trigonelline did not exert estrogenic activity.
Doses up to 10 µmol/L ameliorated the atrophy of neuronal dendrites and axons in amyloid β-peptide-treated female, hemizygous transgenic 5XFAD Alzheimer’s disease mice model [73]. Additionally, trigonelline (30 µmol/L) improved functional neurite outgrowth in human neuroblastoma SK-N-SH cells after treatment for six days [75][84]. Furthermore, daily oral administration of 500 mg/kg bw for 15 days was demonstrated to improve memory retention in six-week-old amyloid β-peptide-treated male ddY mice [85]. Thus, trigonelline is believed to improve cognition in Alzheimer’s disease model laboratory animals [84][86]. Furthermore, it has been discussed that trigonelline may protect against cerebral ischemia [87] by positively modulating neuronal spike frequency [88], stimulating the release of dopamine [89], competitively inhibiting γ-aminobutyric acid (GABA) A-receptors [90], and weakly hampering acetylcholine esterase [91].
This entry is adapted from the peer-reviewed paper 10.3390/molecules28083460