Biogenic amines: formation, action and toxicity - a review.

Biogenic amines (BA) are organic compounds commonly found in food, plants and animals, as well as microorganisms that are attributed with the production of BAs. They are formed as an effect of a chemical process: the decarboxylation of amino acids. Factors determining the formation of BAs include the availability of free amino acids and the presence of microorganisms that show activity with respect to carrying out the decarboxylation process. On the one hand, BAs are compounds that are crucial for maintaining cell viability, as well as the proper course of the organism's metabolic processes, such as protein synthesis, hormone synthesis and DNA replication. On the other hand, despite their positive effects on the functioning of the organism, an excessive content of BAs proves to be toxic (diarrhea, food poisoning, vomiting, sweating or tachycardia). Moreover, they can accelerate carcinogenesis. Amines are a natural component of plant and animal raw materials. As a result of the proven negative effects of amines on living organisms, the reduction of these compounds should be the subject of scientific research. The present review aims to synthesize and summarize the information currently available on BAs, as well as discuss the interpretation of the results. © 2020 Society of Chemical Industry.

Glucose-regulated protein 75 in foodborne disease models induces renal tubular necrosis.

The incidence of kidney disease has increased rapidly in recent years. One major possible reason for this increase in nephrosis is from foodborne toxins. Since the mechanism of how foodborne toxins are involved in the process of nephrosis is largely unknown, the current study aims to establish a profile for how one of the major toxin threats, ochratoxin A (OTA), induce differential protein expression. In this proteomic study of rat kidneys, 75 kd glucose-regulated protein (Grp75) expression was found to be sensitized by a low concentration of OTA, but inhibited by high doses. In response to OTA, a decrease in Grp75 expression preceded the inhibition of mitochondrial Lon peptidase 1 (Lonp1). Using Grp75 knockdown cell line, it was shown that the inhibition of Grp75 promoted the secretion of kidney injury molecule 1 (Kim1), and suppressed Lonp1 expression in renal injury. Moreover, the acceleration of renal disease was associated with the consumption of Grp75. Our study suggests that the Grp75 protein may be valuable as both a treatment and biomarker for the foodborne diseases that induce renal tubular necrosis. The findings of this research are beneficial for the establishment of nutritional interventions, and the screening of therapeutic targets, in cases of nephrosis.

Histamine, histamine intoxication and intolerance.

Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life.

Selenium and Iodine in Autoimmune Thyroiditis.

Selenium and iodine are essential for thyroid hormone synthesis and function. Selenium, in form of selenocysteine, is found either in the catalytic center of enzymes involved in the protection of the thyroid gland from free radicals originating during thyroid hormone synthesis, and in three different iodothyronine deiodinases catalyzing the activation and the inactivation of thyroid hormones. Iodine is an essential constituent of thyroid hormones and its deficiency causes different disorders that include goiter, hypothyroidism, reduced fertility and alteration in growth, physical and neurological development. These two micronutrients could be involved in the pathogenesis of autoimmune thyroid diseases, a spectrum of pathological conditions including Hashimoto's thryoiditis, post-partum thyroiditis, the so-called painless thyroiditis, Graves' disease and Graves' ophtalmopathy. Aim of this paper is to review the role played by selenium and iodine in autoimmune thyroiditis.

Heliotropium europaeum poisoning in cattle and analysis of its pyrrolizidine alkaloid profile.

Pyrrolizidine alkaloids (PAs) are carcinogenic and genotoxic phytochemicals found exclusively in angiosperms. The ingestion of PA-containing plants often results in acute and chronic toxicities in man and livestock, targeting mainly the liver. During February 2014, a herd of 15-18-month-old mixed-breed beef cattle (n = 73) from the Galilee region in Israel was accidently fed hay contaminated with 12% Heliotropium europaeum (average total PA intake was 33 mg PA/kg body weight/d). After 42 d of feed ingestion, sudden death occurred over a time period of 63 d with a mortality rate of 33%. Necropsy and histopathological examination revealed fibrotic livers and moderate ascites, as well as various degrees of hyperplasia and fibrosis of bile duct epithelial cells. Elevated γ-glutamyl-transferase and alkaline phosphatase levels were indicative of severe liver damage. Comprehensive PA profile determination of the contaminated hay and of native H. europaeum by LC-MS/MS revealed the presence of 30 PAs and PA-N-oxides, including several newly reported PAs and PA-N-oxides of the rinderine and heliosupine class. Heliotrine- and lasiocarpine-type PAs constituted 80% and 18% of the total PAs, respectively, with the N-oxides being the most abundant form (92%). The PA profile of the contaminated hay showed very strong resemblance to that of H. europaeum.

Use of a bio-wipe kit to detect fumonisin B1 in faecal materials.

Fusarium toxins with reference to fumonisin B1 (FB1) have long been regarded as contaminants of maize and maize-based related products. However, when consumed they can cause intoxication, especially in humans. Therefore, effective quantitative methods for assessing the dietary exposure of this toxic fungal metabolite are required. The objective of this investigation was to evaluate the effect on the use of a bio-wipe kit, which is a faecal material collection kit, to detect the presence of FB1. Faecal materials were collected from a rural farming community in Gauteng Province, South Africa. In total, 200 samples of faecal material were analysed for Fusarium species using a serial dilution method, while FB1 was further analysed and quantified by reversed-phase TLC and HPLC. The study showed the presence of 11 different Fusarium species grown on potato dextrose agar culture medium of which F. verticillioides and F. proliferatum, producers of FB1, and F. oxysporum were the dominant species. Fumonisin B1 was recorded at an incidence rate of 65% of the total using TLC. Results from HPLC showed that 84% were positive at different ranges of concentration for FB1. This study supports the use of a bio-wipe as a rapid method to determine human exposure to FB1.

Cellular stress marker alteration and inflammatory response in pigs fed with an ochratoxin contaminated diet.

Aim of this study was to characterize the effects of an ochratoxin A (181 ± 34 ng/g) contaminated diet on growth performances, blood parameters, systemic cytokine levels, cell stress markers and reactivity of immune system of weaned pigs. Growth performance was not affected by OTA consumption even if OTA levels increased in plasma, kidney and liver. OTA diminished the protein content in the serum and increased levels of TNF-alpha and IL-10 in plasma. HO-1 mRNA, indicative for cells stress, was decreased in the kidney but increased in the liver. Additionally, whole blood of the animals of the OTA-group showed a decreased capacity to respond with cytokine expression (mRNA and protein) to ex vivo challenge with LPS. In conclusion our findings indicate that chronic ingestion with OTA-contaminated feed, even at low level, is hazardous for the animal and virtually for human health, pig being an excellent model for human.

Effect of the combined probiotics with aflatoxin B1-degrading enzyme on aflatoxin detoxification, broiler production performance and hepatic enzyme gene expression.

In order to degrade aflatoxin B1 (AFB1), AFB1-degrading microbes (probiotics) such as Lactobacillus casei, Bacillus subtilis and Pichia anomala, and the AFB1-degrading enzyme from Aspergillus oryzae were selected and combined to make feed additive. Seventy-five 43-day-old male Arbor Acres broilers were randomly divided into 5 groups, 15 broilers for each group. The broilers were given with 5 kinds of diets such as the basal diet, 400 µg/kg AFB1 supplement without feed additive, and 200, 400, 800 µg/kg AFB1 supplement with 0.15% feed additive. The feeding experimental period was 30 d, which was used to determine production performance of broilers. In addition, serum, liver and chest muscle were selected for measuring AFB1 residues, gene expressions, microscopic and antioxidant analyses. The results showed that adding 0.15% feed additive in broiler diets could significantly relieve the negative effect of AFB1 on chicken's production performance and nutrient metabolic rates (P<0.05). It could also improve AFB1 metabolism, hepatic cell structure, antioxidant activity, and many hepatic enzyme gene expressions involved in oxidoreductase, apoptosis, cell growth, immune system and metabolic process (P<0.05). It could be concluded that the feed additive was able to degrade AFB1 and improve animal production.

Change in kidney damage biomarkers after 13 weeks of exposing rats to the complex of Paecilomyces sinclairii and its host Bombyx mori larvae.

Complex of Paecilomyces sinclairii and host larvae, Bombyx mori, is a well known health food; however, concerns about nephrotoxicity have been raised. Kidney toxicity was investigated after 13 weeks of administering the complex orally to rats with parameters including blood urea nitrogen (BUN), creatinine, and kidney damage biomarkers, beta-2-microglobulin (ß2m), glutathione S-transferase alpha (GST-α), kidney injury molecule 1 (KIM-1), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), vascular endothelial growth factor (VEGF), calbindin, clusterin, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin. Dose-dependent kidney cell karyomegaly and tubular hypertrophy were observed, with higher severity in males. There was a dose-dependent increase in KIM-1 and TIMP-1 levels in kidney and urinary KIM-1, cystatin C, ß2m, and osteopontin levels. KIM-1 and TIMP-1 increased in male kidneys had not recovered by 2 weeks after stopping exposure. Cystatin C in kidney was significantly lowered in all treatment groups at 13 weeks of administration. All the changes were more noticeable in males. These data indicate that the complex damage renal tubule cells with histopathological lesions and changes in biomarker levels. Kidney and urinary KIM-1 and cystatin C were the most markedly affected and early increased indicators among biomarkers tested, whereas BUN and creatinine were not affected.

Aquilegia vulgaris L. extract counteracts oxidative stress and cytotoxicity of fumonisin in rats.

Exposure to fumonisins (FB) is known to have toxic and carcinogenic effects in different animal species, and to express toxicity in cells via the induction of oxidative stress. The aim of the current study was to evaluate the protective effects of the ethanol extract of Aquilegia vulgaris L. against the oxidative stress and the genotoxicity using micronucleus assay and random amplified polymorphism DNA (RAPD-PCR) in FB-treated rats. Sixty mature female Sprague-Dawley were divided into six treatment groups and treated for 4 weeks as follow: the control group, the group fed FB-contaminated diet (200 mg/kg diet), the groups treated orally with the extract (5 and 10 mg/kg bw) and the groups fed FB-contaminated diet and treated with the extract at the two doses. The results showed that treatment with FB alone disturbed lipid profile in serum, increases Sa/So ratio, induces micronucleated polychromatic erythrocytes (Mn-PCEs) in bone marrow, increases DNA and RNA in liver accompanied with significant changes in histological picture The extract alone at the two tested doses did not induce any significant changes in the biochemical or histological picture. The combined treatment showed significant improvements in all biochemical, cytogenetic parameters tested and histological pictures in the liver tissues. Moreover, this improvement was more pronounced in the group received the high dose of the extract. It could be concluded that the ethanol extract of A. vulgaris induced its protective effect via the increase in the antioxidant capacity, inhibition of lipid peroxidation and scavenging of free radicals.

Generation of quinoneimine intermediates in the bioactivation of 3-(N-phenylamino)alanine (PAA) by human liver microsomes: a potential link between eosinophilia-myalgia syndrome and toxic oil syndrome.

Eosinophilia-myalgia syndrome (EMS) was an intoxication episode that occurred in the US in 1989 and affected 1,500 people. EMS was associated with the ingestion of manufactured L-tryptophan, and 3-(N-phenylamino)alanine (PAA) was identified as one of the contaminants present in the L-tryptophan batches responsible for intoxication. In previous studies (Martínez-Cabot et al., Chem Res. Toxicol., in press), we have shown that the incubation of 3-(N-phenylamino)propane-1,2-diol (PAP), a toxic biomarker of the oil batches that caused Toxic Oil Syndrome in Spain, with human liver microsomes generates a reactive quinoneimine intermediate. The structural similarity between PAA and PAP led Mayeno and co-workers (Mayeno et al. (1995) Chem. Res. Toxicol. 8, 911-916) to hypothesize that both xenobiotics could be linked to a common etiologic agent. We thus set about to study the bioactivation of PAA by human liver microsomes. Under these conditions, PAA is converted to its 4'-hydroxy derivative, an unstable intermediate that is rapidly transformed into the final metabolites 4-aminophenol and formylglycine, which were identified in the incubations by GC/MS using the H2(18)O-labeled medium. We also provide evidence that 4-aminophenol and formylglycine are formed from a quinoneimine intermediate via a pathway similar to that demonstrated for PAP bioactivation. This quinoneimine, in the absence of nucleophiles in the incubation medium, could isomerize to give the corresponding imine, which could undergo hydrolysis to yield the aforementioned final products. These findings establish that EMS and TOS are linked by a common toxic metabolite (4-aminophenol) and that they may be further linked by the concomitant release of potentially hazardous carbonyl species.

In vitro bioactivation of 3-(N-phenylamino)propane-1,2-diol by human and rat liver microsomes and recombinant P450 enzymes. Implications for toxic oil syndrome.

Toxic oil syndrome (TOS) was a massive food-borne intoxication that occurred in Spain in 1981. Epidemiological studies imputed 3-( N-phenylamino)propane-1,2-diol (PAP) derivatives as the toxic agents. The in vitro bioactivation of PAP by rat and human liver microsomes was studied. In both cases, 3-[ N-(4'-hydroxyphenyl)amino]propane-1,2-diol ( 1) was detected as the main metabolite. Inhibition studies with pooled human liver microsomes in the presence and absence of P450-specific inhibitors suggest that 2C8 and 2E1 are the main enzymes involved in PAP bioactivation, followed by 3A4/5, 1A1/2, and 2C9. Incubations of PAP with 10 different recombinant P450 enzymes showed that 2C8, 2C9, 2C18, 2D6, and 2E1 catalyzed PAP 4'-hydroxylation. Incubations of phenol 1 with rat and human liver microsomes in the presence of GSH resulted in the formation of a glutathione conjugate of a quinoneimine metabolite derived from 1. In rat liver microsomes, P450 enzymes play a key role in the bioactivation of 1, whereas in human liver microsomes, autoxidation appears to be the major mechanism. The implications of these results for toxic oil syndrome are discussed.

Synthesis and stability studies of the glutathione and N-acetylcysteine adducts of an iminoquinone reactive intermediate generated in the biotransformation of 3-(N-phenylamino)propane-1,2-diol: implications for toxic oil syndrome.

Epidemiological studies have pointed to fatty acid mono- and diesters of 3-(N-phenylamino)propane-1,2-diol (PAP) as the biomarkers of the toxic oil batches that caused toxic oil syndrome (TOS), an intoxication episode that occurred in Spain in 1981, causing over 400 deaths and affecting more than 20000 people. The biotransformation of PAP administered intraperitoneally to two mouse strains produced potentially toxic metabolites. The identification of 3-(4'-hydroxyphenylamino)propane-1,2-diol among those metabolites was important because the compound can generate the quinoneimine intermediate 2. The potential toxicity of quinoneimines has been attributed primarily to their electrophilic character. Accordingly, the reactions of 2 with N-acetylcysteine, N-acetylcysteine methyl ester, and GSH were investigated. Quinoneimine 2 reacts with the N-acetylcysteine methyl ester to give the expected conjugate as a major product, accompanied by the corresponding bis and tris adducts. The monoadduct, when isolated in pure form, undergoes spontaneous oxidation to generate a new quinoneimine intermediate, which in turn rearranges and undergoes hydrolysis to afford the thiol adduct formally derived from the quinoneimine generated from p-aminophenol. The same overall pathway was observed for the reaction of 2 with N-acetylcysteine and GSH. Both thiol reagents reacted with the quinoneimine to give the corresponding adducts in which the addition took place at the ortho position with respect to the amino group. These conjugates were also unstable and ultimately afforded the corresponding adduct derived from p-aminophenol. The relevancy of these results to TOS, as well as their potential generalization for quinoneimines derived from other xenobiotics, is discussed herein.

Metabolism of R,S enantiomers of 3-phenylamino-1,2-propanediol, a compound associated with the toxic oil syndrome, in C57BL/6- and A/J-strain mice.

PAP, a very polar substance, is highly metabolized in mice and excreted principally in urine in the form of the 2-hydroxy-3-phenylaminopropanoic acid of each enantiomer. Thus, the major route of PAP elimination in these strains is alkyl chain oxidation. In particular, S-PAP is eliminated principally in the form of that metabolite, whereas R-PAP enantiomer showed further oxidized species at the aromatic ring and alkyl chain, yielding potential decarboxylated compounds and iminoquinones. All these metabolites may have toxicologic implications. On the other hand, OOPAP intestinal hydrolysis in favour of one PAP enantiomer might be expected since lipases show chiral hydrolysis (unpublished data, manuscript in preparation). In this respect, enantiomeric distribution and metabolic differences should be taken into account in the toxicokinetics of these compounds and their potential association with Toxic Oil Syndrome symptoms.

Fatty acid anilides: in vivo formation and relevance to toxic oil syndrome.

Toxic oil syndrome (TOS), a multisystemic epidemic outbreak in 1981 in Spain, was caused by the ingestion of a cooking oil mixture containing rapeseed oil denatured with aniline. The mechanisms and causative agents responsible for the TOS are still not known. Although primary lesions observed in TOS patients could not be reproduced experimentally, the levels of fatty acid anilides (FAAs) and aniline in TOS-related cooking oil were considered proximate markers of TOS. Aniline, available from free aniline and FAAs ingested with TOS-related cooking oil, and its reconjugation with endogenous fatty acids could be an early event leading to TOS. Therefore, the present study was undertaken to determine the formation of FAAs following an oral dose of 2 mmol/kg aniline hydrochloride (AH) via gavage in rats. Here, 16:0, 18:0, 18:1, 18:2, 18:3, and 20:4 FAAs were analyzed in the whole blood, brown fat, liver, and pancreas at 0 (control), 0.25, 0.5, 1, 3, 6, 12, 24, and 48 hours. Generally, 16:0 and 18:1 FAAs were detected in the whole blood, brown fat, and liver of AH-treated rats with highest mean levels at 0.25 or 0.5 hour, except 3 hours for the whole blood. Only 16:0 FAA was detectable in the pancreas of AH-treated animals. The 18:0 FAA was also detected frequently in the liver while other FAAs were either in trace amounts or not detectable in the tissues analyzed in the present study. Overall, highest formation of the 16:0 FAA was found in the liver followed by pancreas and of 18:1 FAA in the whole blood and brown fat. These results indicate a rapid formation and further metabolism and disposition of FAAs in rat model and support our previous findings that 18:1 and 16:0 fatty acids are better substrates for the conjugation with aniline. Surprisingly, a small or trace amount of a few FAAs also detected in the tissues of control rats indicates their endogenous biosynthesis and/or presence. Results of 18:1 fatty acid incubation and aniline in the presence of fatty acid ethyl ester synthase, purified to homogeneity from rat liver microsome, suggest that formation of FAAs is catalyzed by an enzyme involved in the conjugation of fatty acids with xenobiotic alcohols. Because the FAAs are known to exert a wide range of toxicity in experimental animals and primary cell cultures, in vivo formation of FAAs could be an early event leading to TOS.

Biotransformation of 3-(phenylamino)-1,2-propanediol to 3-(phenylamino)alanine: a chemical link between toxic oil syndrome and eosinophilia-myalgia syndrome.

During late 1989, the eosinophilia-myalgia syndrome (EMS) developed as an epidemic in the United States, with numerous additional cases reported in several other countries worldwide. Eight years earlier, a closely-related disease, the toxic oil syndrome (TOS), occurred in Spain as a massive food-borne epidemic. Although EMS was linked to the ingestion of tainted L-tryptophan, and TOS to aniline-denatured rapeseed oil, the etiologic agent(s) responsible for both diseases remains undetermined. Contaminants in these foodstuffs are believed to have triggered the diseases. Aniline contaminants, including 3-(phenylamino)-1,2-propanediol (PAP), have been reported in oil used by patients who developed TOS. A related aniline derivative, 3-(phenylamino)-L-alanine (PAA), was recently isolated from L-tryptophan associated with the onset of EMS. Here, we demonstrate the biotransformation of PAP into PAA by both rat hepatocytes and human liver tissue. The structural characterization of PAA was unequivocally determined using on-line HPLC coupled with atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS). This finding is the first reported chemical link between TOS and EMS and suggests that these two related diseases share a common etiology, namely, PAA.

[Protective effect of selenium in acute T-2 mycotoxicosis]. / Zashchitnoe deistvie selena pri ostrom T-2-mikotoksikoze.

Male Wistar rats were fed diets supplemented with selenium (0.5 and 2.5 mg/kg) for 6 weeks. When T-2 toxin was administered at 3.8 mg/kg body weight; sings of intoxication were less distinct in rats fed selenium-supplemented diets. Mortality caused by T-2 toxin was two times lower if selenium content amounted to 2.5 mg/kg. The level of cytochrome P-450 and the rate of deethylation of 7-ethoxycoumarin were considerably decreased in the liver of rats that received T-2 toxin and fed a diet with high selenium content. At the same time the activity of epoxide hydrolase and UDP-glucuronosyltransferase was significantly higher (1.6 and 1.7 times more) as compared with unsupplemented group. The results obtained allow to assume that there is a relationship between the decrease of T-2 toxin toxicity and the change in its metabolism in rats fed selenium-supplemented diets.