RESUMEN
Methionine is an essential amino acid needed for a variety of processes in living organisms. Ionizing radiation depletes tissue methionine concentrations and leads to the loss of DNA methylation and decreased synthesis of glutathione. In this study, we aimed to investigate the effects of methionine dietary supplementation in CBA/CaJ mice after exposure to doses ranging from 3 to 8.5 Gy of 137Cs of total body irradiation. We report that mice fed a methionine-supplemented diet (MSD; 19.5 vs. 6.5 mg/kg in a methionine-adequate diet, MAD) developed acute radiation toxicity at doses as low as 3 Gy. Partial body irradiation performed with hindlimb shielding resulted in a 50% mortality rate in MSD-fed mice exposed to 8.5 Gy, suggesting prevalence of radiation-induced gastrointestinal syndrome in the development of acute radiation toxicity. Analysis of the intestinal microbiome demonstrated shifts in the gut ecology, observed along with the development of leaky gut syndrome and bacterial translocation into the liver. Normal gut physiology impairment was facilitated by alterations in the one-carbon metabolism pathway and was exhibited as decreases in circulating citrulline levels mirrored by decreased intestinal mucosal surface area and the number of surviving crypts. In conclusion, we demonstrate that a relevant excess of methionine dietary intake exacerbates the detrimental effects of exposure to ionizing radiation in the small intestine.NEW & NOTEWORTHY Methionine supplementation, instead of an anticipated health-promoting effect, sensitizes mice to gastrointestinal radiation syndrome. Mechanistically, excess of methionine negatively affects intestinal ecology, leading to a cascade of physiological, biochemical, and molecular alterations that impair normal gut response to a clinically relevant genotoxic stressor. These findings speak toward increasing the role of registered dietitians during cancer therapy and the necessity of a solid scientific background behind the sales of dietary supplements and claims regarding their benefits.
Asunto(s)
Síndrome de Radiación Aguda/etiología , Suplementos Dietéticos/toxicidad , Intestino Delgado/efectos de los fármacos , Metionina/toxicidad , Traumatismos Experimentales por Radiación/etiología , Síndrome de Radiación Aguda/metabolismo , Síndrome de Radiación Aguda/microbiología , Síndrome de Radiación Aguda/patología , Animales , Metilación de ADN/efectos de los fármacos , Disbiosis , Metabolismo Energético/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Intestino Delgado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Dosis de Radiación , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/microbiología , Traumatismos Experimentales por Radiación/patología , Factores de Riesgo , Irradiación Corporal TotalRESUMEN
A fundamental component for success in drug discovery is the ability to assemble and screen compounds that encompass a broad swath of biologically relevant chemical-diversity space. Achieving this goal in a natural-products-based setting requires access to a wide range of biologically diverse specimens. For this reason, we introduced a crowdsourcing program in which citizen scientists furnish soil samples from which new microbial isolates are procured. Illustrating the strength of this approach, we obtained a unique fungal metabolite, maximiscin, from a crowdsourced Alaskan soil sample. Maximiscin, which exhibits a putative combination of polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), and shikimate pathway components, was identified as an inhibitor of UACC-62 melanoma cells (LC50=0.93 µM). The metabolite also exhibited efficacy in a xenograft mouse model. These results underscore the value of building cooperative relationships between research teams and citizen scientists to enrich drug discovery efforts.
Asunto(s)
Antineoplásicos/metabolismo , Productos Biológicos/metabolismo , Hongos/metabolismo , Metionina/metabolismo , Tirosina/metabolismo , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Productos Biológicos/uso terapéutico , Productos Biológicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Melanoma/tratamiento farmacológico , Metionina/química , Metionina/toxicidad , Ratones , Conformación Molecular , Péptido Sintasas/metabolismo , Policétidos/química , Policétidos/metabolismo , Pseudomonas/metabolismo , Ácido Shikímico/química , Ácido Shikímico/metabolismo , Trasplante Heterólogo , Tirosina/química , Tirosina/toxicidadRESUMEN
Hypermethioninemic patients exhibit a variable degree of neurological dysfunction. However, the mechanisms involved in these alterations have not been completely clarified. Cholinergic system has been implicated in many physiological processes, including cognitive performances, as learning, and memory. Parameters of cholinergic signaling have already been characterized in zebrafish brain. Since zebrafish is a small freshwater teleost which is a vertebrate model for modeling behavioral and functional parameters related to human pathogenesis and for clinical treatment screenings, in the present study we investigated the effects of short- and long-term methionine exposure on cognitive impairment, AChE activity and gene expression in zebrafish. For the studies, animals were exposed at two methionine concentrations (1.5 and 3.0 mM) during 1 h or 7 days (short- or long-term treatments, respectively). We observed a significant increase in AChE activity of zebrafish brain membranes after long-term methionine exposure at 3.0 mM. However, AChE gene expression decreased significantly in both concentrations tested after 7 days of treatment, suggesting that post-translational events are involved in the enhancement of AChE activity. Methionine treatment induces memory deficit in zebrafish after long-term exposure to this amino acid, which could be related, at least in part, with cognitive impairment observed in hypermethioninemia. Therefore, the results here presented raise a new perspective to use the zebrafish as a complementary vertebrate model for studying inborn errors of metabolism, which may help to better understand the pathophysiology of this disease.
Asunto(s)
Acetilcolinesterasa/metabolismo , Reacción de Prevención , Trastornos de la Memoria/inducido químicamente , Metionina/administración & dosificación , Animales , Secuencia de Bases , Encéfalo/enzimología , Cartilla de ADN , Trastornos de la Memoria/enzimología , Metionina/toxicidad , Reacción en Cadena de la Polimerasa , Pez CebraRESUMEN
Methionine is a component of one-carbon metabolism and a precursor of S-adenosylmethionine (SAM), the methyl donor for DNA methylation. When methionine intake is high, an increase of S-adenosylmethionine (SAM) is expected. DNA methyltransferases convert SAM to S-adenosylhomocysteine (SAH). A high intracellular SAH concentration could inhibit the activity of DNA methyltransferases. Therefore, high methionine ingestion could induce DNA damage and change the methylation pattern of tumor suppressor genes. This study investigated the genotoxicity of a methionine-supplemented diet. It also investigated the diet's effects on glutathione levels, SAM and SAH concentrations and the gene methylation pattern of p53. Wistar rats received either a methionine-supplemented diet (2% methionine) or a control diet (0.3% methionine) for six weeks. The methionine-supplemented diet was neither genotoxic nor antigenotoxic to kidney cells, as assessed by the comet assay. However, the methionine-supplemented diet restored the renal glutathione depletion induced by doxorubicin. This fact may be explained by the transsulfuration pathway, which converts methionine to glutathione in the kidney. Methionine supplementation increased the renal concentration of SAH without changing the SAM/SAH ratio. This unchanged profile was also observed for DNA methylation at the promoter region of the p53 gene. Further studies are necessary to elucidate this diet's effects on genomic stability and DNA methylation.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Suplementos Dietéticos/toxicidad , Genes p53/efectos de los fármacos , Inestabilidad Genómica/efectos de los fármacos , Metionina/toxicidad , Animales , Doxorrubicina/antagonistas & inhibidores , Glutatión/metabolismo , Riñón/metabolismo , Masculino , Metionina/farmacología , Regiones Promotoras Genéticas/efectos de los fármacos , Ratas , Ratas Wistar , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismoRESUMEN
Boars fed on ration of 200 ppm Zn methionate showed a significant increase (P < 0.001) in sperm DNA fragmentation when compared to animals fed on non-supplemented and rations containing 150 ppm Zn methionate. There was a positive correlation (R2 = 0.207; P = 0.002) between % sperm DNA fragmentation (SDF) and the concentration of Zn in spermatozoa. Increased Zn in the diet also resulted in a non-proportional increase in Zn concentration in the testis and spermatozoa but not in the epididymis; Zn in sperm accumulated at levels up to 50 times higher than that found in the seminal plasma and 10-13 times that found in the epididymis and testis, respectively. These results show that supplementation of dietary Zn at a concentration of 200 ppm had an adverse effect on boar sperm DNA quality and may be related to the ability of spermatozoa to accumulate Zn during spermiogenesis.
Asunto(s)
Fragmentación del ADN/efectos de los fármacos , Suplementos Dietéticos/toxicidad , Epidídimo/efectos de los fármacos , Metionina/análogos & derivados , Compuestos Organometálicos/toxicidad , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Análisis de Varianza , Animales , Epidídimo/metabolismo , Epidídimo/patología , Análisis de los Mínimos Cuadrados , Masculino , Metionina/metabolismo , Metionina/toxicidad , Compuestos Organometálicos/metabolismo , Espermatogénesis/efectos de los fármacos , Espermatozoides/metabolismo , Espermatozoides/patología , Sus scrofa , Testículo/metabolismo , Testículo/patología , Factores de Tiempo , Distribución Tisular , Regulación hacia ArribaRESUMEN
Schizophrenia postmortem brain is characterized by gamma aminobutyric acid downregulation and by decreased dendritic spine density in frontal cortex. Protracted L-methionine treatment exacerbates schizophrenia symptoms, and our earlier work (Tremolizzo et al. and Dong et al.) has shown that L-methionine decreases reelin and GAD67 transcription in mice which is prevented by co-administration of valproate. In this study, we observed a decrease in spine density following L-methionine treatment, which was prevented by co-administration of valproate. Together with our earlier findings conducted under the same experimental conditions, we suggest that downregulation of spine density in L-methionine-treated mice may be because of the decreased expression of reelin and that valproate may prevent spine downregulation by inhibiting the methylation induced decrease in reelin.
Asunto(s)
Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/patología , Metionina/toxicidad , Esquizofrenia/patología , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Moléculas de Adhesión Celular Neuronal/efectos de los fármacos , Moléculas de Adhesión Celular Neuronal/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Forma de la Célula/efectos de los fármacos , Forma de la Célula/fisiología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Interacciones Farmacológicas/fisiología , Proteínas de la Matriz Extracelular/efectos de los fármacos , Proteínas de la Matriz Extracelular/metabolismo , Lóbulo Frontal/fisiopatología , GABAérgicos/farmacología , GABAérgicos/uso terapéutico , Masculino , Metionina/metabolismo , Metilación/efectos de los fármacos , Ratones , Proteínas del Tejido Nervioso/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neurotoxinas/metabolismo , Neurotoxinas/toxicidad , Proteína Reelina , Esquizofrenia/inducido químicamente , Esquizofrenia/fisiopatología , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/patología , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
Animal studies have shown that several methionine (Met) and cysteine (Cys) analogs or precursors have L-Met- and L-Cys-sparing activity. Relative oral bioavailability (RBV) values, with the L-isomer of Met and Cys set at 100% (isosulfurous basis), are near 100% for D-Met for animals but only about 30% for humans. Both the OH and keto analogs of Met have high RBV-sparing values, as does N-acetyl-L-Met (the D-isomer of acetylated Met has no bioactivity). L-Homocysteine has an RBV value of about 65% for Met sparing in rats and chicks, but D-homocysteine has little if any Met-sparing activity. S-Methyl-L-Met can partially spare Met, but only when fed under dietary conditions of choline/betaine deficiency. Relative to L-Cys, high RBV values exist for L-cystine, N-acetyl-L-Cys, L-homocysteine, L-Met, and glutathione, but D-cystine, the keto analog of Cys, L-cysteic acid, and taurine have no Cys-sparing activity. l-2-Oxothiazolidine-4-carboxylate has an RBV value of 75%, D-homocysteine 70%, and DL-lanthionine 35% as Cys precursors. Under dietary conditions of Cys deficiency and very low inorganic sulfate (SO4) ingestion, dietary SO4 supplementation has been shown to reduce the Cys requirement of several animal species as well as humans. Excessive ingestion of Met, Cys, or cystine has also been studied extensively in experimental animals, and these sulfur amino acids (SAA) are well established as being among the most toxic of all amino acids that have been studied. Even though Cys and its oxidized product (cystine) are equally efficacious at levels at or below their dietary requirements for maximal growth, Cys is far more toxic than cystine when administered orally in the pharmacologic dosing range. Isosulfurous (excess) levels of cystine, N-acetyl-L-Cys, or glutathione are far less growth depressing than L-Cys when 6 to 10 times the minimally required level of these SAA compounds are fed to chicks.
Asunto(s)
Aminoácidos Sulfúricos/metabolismo , Aminoácidos Sulfúricos/toxicidad , Especificidad de la Especie , Alanina/administración & dosificación , Alanina/análogos & derivados , Alanina/análisis , Aminoácidos Sulfúricos/farmacocinética , Animales , Disponibilidad Biológica , Cisteína/administración & dosificación , Cisteína/metabolismo , Cisteína/toxicidad , Cistina/administración & dosificación , Suplementos Dietéticos , Glutatión/administración & dosificación , Glutatión/análisis , Homocisteína/metabolismo , Humanos , Hidroxilación , Isomerismo , Metionina/administración & dosificación , Metionina/metabolismo , Metionina/toxicidad , Sulfuros/administración & dosificación , Sulfuros/análisis , Taurina/administración & dosificación , Taurina/análisis , Vitamina U/administración & dosificación , Vitamina U/análisisRESUMEN
The adequacy range of dietary requirements of specific amino acids in disease states is difficult to determine. In health, several techniques are available allowing rather precise quantification of requirements based on growth of the organism, rises in plasma concentration, or increases in the oxidation of marker amino acids during incremental administration of the amino acid under study. Requirements may not be similar in disease with regard to protein synthesis or with regard to specific functions such as scavenging of reactive oxygen species by compounds including glutathione. Requirements for this purpose can be assessed only when such a function can be measured and related to clinical outcome. There is apparent consensus concerning normal sulfur amino acid (SAA) requirements. WHO recommendations amount to 13 mg/kg per 24 h in healthy adults. This amount is roughly doubled in artificial nutrition regimens. In disease or after trauma, requirements may be altered for methionine, cysteine, and taurine. Although in specific cases of congenital enzyme deficiency, prematurity, or diminished liver function, hypermethionemia or hyperhomocysteinemia may occur, SAA supplementation can be considered safe in amounts exceeding 2-3 times the minimal recommended daily intake. Apart from some very specific indications (e.g., acetaminophen poisoning), the usefulness of SAA supplementation is not yet established. There is a growing body of data pointing out the potential importance of oxidative stress and resulting changes in redox state in numerous diseases including sepsis, chronic inflammation, cancer, AIDS/HIV, and aging. These observations warrant continued attention for the potential role of SAA supplementation. In particular, N-acetylcysteine remains promising for these conditions.
Asunto(s)
Aminoácidos Sulfúricos/administración & dosificación , Aminoácidos Sulfúricos/toxicidad , Biomarcadores/análisis , Nutrición Enteral , Necesidades Nutricionales , Nutrición Parenteral , Aminoácidos Sulfúricos/metabolismo , Animales , Cisteína/administración & dosificación , Cisteína/deficiencia , Cisteína/toxicidad , Suplementos Dietéticos , Glutatión/biosíntesis , Glutatión/metabolismo , Homocisteína/metabolismo , Humanos , Metionina/deficiencia , Metionina/metabolismo , Metionina/toxicidad , Azufre/metabolismo , Taurina/deficienciaRESUMEN
Methylation of DNA occurs at cytosines within CpG (cytosine-guanine) dinucleotides and is 1 of several epigenetic mechanisms that serve to establish and maintain tissue-specific patterns of gene expression. The methyl groups transferred in mammalian DNA methylation reactions are ultimately derived from methionine. High dietary methionine intake might therefore be expected to increase DNA methylation. Because of the circular nature of the methionine cycle, however, methionine excess may actually impair DNA methylation by inhibiting remethylation of homocysteine. Although little is known regarding the effect of dietary methionine supplementation on mammalian DNA methylation, the available data suggest that methionine supplementation can induce hypermethylation of DNA in specific genomic regions. Because locus-specific DNA hypomethylation is implicated in the etiology of various cancers and developmental syndromes, clinical trials of "promethylation" dietary supplements are already under way. However, aberrant hypermethylation of DNA could be deleterious. It is therefore important to determine whether dietary supplementation with methionine can effectively support therapeutic maintenance of DNA methylation without causing excessive and potentially adverse locus-specific hypermethylation. In the viable yellow agouti (Avy) mouse, maternal diet affects the coat color distribution of offspring by perturbing the establishment of methylation at the Avy metastable epiallele. Hence, the Avy mouse can be employed as a sensitive epigenetic biosensor to assess the effects of dietary methionine supplementation on locus-specific DNA methylation. Recent developments in epigenomic approaches that survey locus-specific DNA methylation on a genome-wide scale offer broader opportunities to assess the effects of high methionine intake on mammalian epigenomes.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Dieta , Metionina/administración & dosificación , Animales , Suplementos Dietéticos , Epigénesis Genética/genética , Regulación de la Expresión Génica , Metionina/toxicidad , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismoRESUMEN
The literature has been searched to identify evidence relating to the possible toxicity of the amino acid methionine in human subjects. Nutritional and metabolic studies have employed amounts of methionine, including the d and dl isomers, both below and above the requirement and have not reported adverse effects in adults and children. Although methionine is known to exacerbate psychopathological symptoms in schizophrenic patients, there is no evidence of similar effects in healthy subjects. The role of methionine as a precursor of homocysteine is the most notable cause for concern. A "loading dose" of methionine (0.1 g/kg) has been given, and the resultant acute increase in plasma homocysteine has been used as an index of the susceptibility to cardiovascular disease. Although this procedure results in vascular dysfunction, this is acute and unlikely to result in permanent damage. However, a 10-fold larger dose, given mistakenly, resulted in death. Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, B-12, C, and folic acid. In infants, methionine intakes of 2-5 times normal resulted in impaired growth and extremely high plasma methionine levels, but no adverse long-term consequences were observed.
Asunto(s)
Metionina/toxicidad , Cistationina/metabolismo , Dieta , Endotelio Vascular/efectos de los fármacos , Homocisteína/sangre , Homocisteína/metabolismo , Humanos , Lactante , Fenómenos Fisiológicos Nutricionales del Lactante , Metionina/administración & dosificación , Metionina/metabolismo , Fenómenos Fisiológicos de la Nutrición , Necesidades NutricionalesRESUMEN
To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Captopril/farmacología , Enalapril/farmacología , Endotelio Vascular/efectos de los fármacos , Metionina/administración & dosificación , Compuestos de Sulfhidrilo/fisiología , Acetilcisteína/farmacología , Animales , Arildialquilfosfatasa/sangre , Endotelio Vascular/fisiología , Masculino , Malondialdehído/sangre , Metionina/toxicidad , Óxido Nítrico/sangre , Peptidil-Dipeptidasa A/sangre , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/sangre , Vasodilatación/efectos de los fármacosRESUMEN
The occurrence of methionine imbalance and toxicity was examined using 70- and 100-kg Holstein bull calves. The animals had been trained to maintain reflex closure of the reticular groove after weaning at 5 wk of age, and Trials 1 (n = 30) and 2 (n = 24) were conducted on animals at 7 and 12 wk of age, respectively. Calves received a corn-soybean meal diet in Trial 1 and a corn-corn gluten meal diet in Trial 2. In Trial 1, postruminal administration of 6 g of DL-methionine/d increased ADG, feed intake, gain/feed, and N retention compared with a control group receiving N-free supplement. However, the administration of 12 g of DL-methionine/d did not improve these variables, whereas both 18 and 24 g/d resulted in BW loss and decreased gain/feed and N utilization efficiency. In Trial 2, postruminal administration of 16 g/d of L-lysine from L-lysine monohydrochloride increased ADG, gain/feed, and N utilization efficiency compared with a control group receiving a N-free supplement. The administration of 8 g of DL-methionine/d in addition to L-lysine did not exert an adverse effect on these variables. However, the additional supplementation of 16 and 24 g of DLmethionine/d negated the improvement, whereas 32 g/d resulted in BW loss and decreased gain/feed and N utilization efficiency. These results showed that a methionine imbalance and toxicity occurred in calves with even a modest excess of DL-methionine, and 70-kg calves were more susceptible to methionine toxicity than 100-kg calves. Plasma concentrations of branched-chain amino acids and phenylalanine linearly decreased with increasing amounts of additional DL-methionine from 0 to 32 g/d in Trial 2. However, such a decrease occurred mainly within the range from 0 to 12 g/d in Trial 1. This decrease was suggested to occur in relation to methionine metabolism via the transsulfuration pathway.
Asunto(s)
Alimentación Animal , Bovinos/metabolismo , Metionina/toxicidad , Aminoácidos/sangre , Animales , Peso Corporal , Bovinos/sangre , Proteínas en la Dieta/administración & dosificación , Proteínas en la Dieta/farmacología , Suplementos Dietéticos , Homeostasis , Masculino , Glycine maxRESUMEN
The metabolism of the polyamines spermidine and spermine is known to be enhanced in rapidly proliferating cells. Methionine is a precursor of the aminopropyl moieties of these amines. Therefore, it was of interest to study the effects of a methionine supplemented diet on polyamine metabolism and preneoplastic changes occurring in the intestinal tract of rats treated with the chemical carcinogen azoxymethane (AOM). Adult Wistar rats received 15 mg AOM/kg body wt (i.p.) once each week for 2 weeks. Thereafter, the rats were randomly divided into two groups and received controlled isoenergetic diets containing the same amount of folate, choline and vitamin B12 during 12 weeks: one group was kept on a standard diet; the other was fed the same diet, except that 1% L-methionine was added at the expense of carbohydrates. After 12 weeks, the administration of the methionine-supplemented diet stimulated the turnover rate of ileal epithelial cells, indicating enhanced crypt cell proliferation. Furthermore, in this group, a 2-fold increase in the number of aberrant hyperproliferative crypts and the appearance of tumors was observed in the colon. These effects were accompanied by the increased formation of spermidine and spermine due to the enhancement of S-adenosylmethionine decarboxylase activity and by the upregulation of Cdx-1, a homeobox gene with oncogenic potentials. The experimental data do not support the view of a chemopreventive effect of dietary methionine supplementation on intestinal carcinogenesis in rats, even at an early phase of preneoplastic development, but rather suggest that methionine promotes intestinal carcinogenesis.
Asunto(s)
Proteínas Aviares , Dieta , Neoplasias Intestinales/inducido químicamente , Metionina/toxicidad , Animales , Secuencia de Bases , Factor de Transcripción CDX2 , Movimiento Celular , Cartilla de ADN , Proteínas de Homeodominio/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Neoplasias Intestinales/metabolismo , Masculino , Metionina/administración & dosificación , Poliaminas/metabolismo , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/metabolismo , ARN Mensajero/genética , Ratas , Ratas Wistar , TransactivadoresRESUMEN
Two experiments with Sprague Dawley rats tested their ability to hydrolyse myristoyl-methionine (M-M) into myristic acid and L-methionine (M). In the first experiment, lasting for 3 days. male rats were orally administered [9,10-3H]myristoyl-L-[35S]methionine. The recovery of radioactivity was approximately 90% for both isotopes; 19% of the administered 3H was recovered in the urine and 16% in the faeces, while the recovered 35S activity was 13 and 12%, respectively. The balance of the radioactivity was found among the tissues, organs and blood. In the second experiment, male and female rats received soybean-based diets which were supplemented with either 0.305% M-M or 0.2% M (both diets contained equal amounts of M) for periods up to 4 weeks. The growth rate of the rats receiving the 0.305% M-M diets was slightly slower than that for the rats on the 0.2% M diet, but the difference was not statistically significant (P > 0.05). The M-M rats had a transitory decrease in feed consumption, suggesting that palatability may have contributed to the growth difference and that a somewhat greater amount of M-M was necessary for the rat to attain the same growth rate as that produced by 0.2% M. When the amount of dietary M-M was increased to 3.05% M-M, a greater reduction in feed consumption and body weight gain was observed. This latter diet was an initial attempt to study the potential toxicity of M-M. None of the haematological, clinical chemistry or organ weight data suggested that M-M was overtly toxic per se, but longer-term feeding studies are needed to evaluate the potential toxicity of M-M more fully.
Asunto(s)
Antiinflamatorios no Esteroideos/metabolismo , Metionina/análogos & derivados , Ácidos Mirísticos/metabolismo , Administración Oral , Alimentación Animal , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/toxicidad , Biomarcadores/sangre , Biomarcadores/orina , Peso Corporal/efectos de los fármacos , Dieta , Suplementos Dietéticos , Ingestión de Alimentos/efectos de los fármacos , Heces/química , Femenino , Masculino , Metionina/metabolismo , Metionina/farmacocinética , Metionina/toxicidad , Ácidos Mirísticos/farmacocinética , Ácidos Mirísticos/toxicidad , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Radioisótopos de Azufre , Distribución Tisular , TritioRESUMEN
Rats were fed toxic levels of methionine with or without simultaneous dietary supplements of glycine and serine. Feed intake, growth rate, and metabolite concentrations in intestine, plasma, liver, skeletal muscle, and kidneys were monitored. Both toxic amounts of methionine and supplemental glycine and serine affected the tissue distribution of several amino acids resulting in similar, opposite, and diet-specific effects on the parameters studied. These changes were considered to be normal responses of amino acid metabolism to diet and to reflect metabolite flows between tissues. The feeding of toxic levels of methionine resulted in the accumulation of methionine, taurine, and glutathione in all tissues measured, but caused marked accumulation of S-adenosylmethionine and its catabolites only in liver. Hepatic accumulation of S-adenosylmethionine was accompanied by 40% stimulation of methionine adenosyltransferase and 40% repression of spermine synthase over a 2-week period. Simultaneous dietary supplements of glycine and serine combined with toxic levels of methionine markedly stimulated hepatic methionine catabolism. As a result, tissue distribution of methionine and glutathione returned close to normal in all tissues measured and accumulation of hepatic S-adenosylmethionine and its catabolites was prevented. Concentrations of taurine in liver, blood, and kidneys were further elevated, suggesting increased conversion of methionine to taurine followed by urinary excretion. These changes were accompanied by normalization of the above enzyme activities and the absence of symptoms of methionine toxicity. It was concluded that methionine toxicity is likely to be linked to hepatic accumulation of S-adenosylmethionine, resulting in liver dysfunction probably due to nonenzymatic methylation of liver macromolecules. Accumulation of tissue glutathione may also contribute to toxicity.
Asunto(s)
Aminoácidos/metabolismo , Dieta , Glicina/farmacología , Hígado/metabolismo , Metionina/toxicidad , S-Adenosilmetionina/metabolismo , Serina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Glicina/administración & dosificación , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Masculino , Músculos/efectos de los fármacos , Músculos/metabolismo , Ratas , Ratas Wistar , Serina/administración & dosificaciónRESUMEN
Two groups (n = 5) of male weanling Wistar rats were housed individually and fed copper (Cu)-deficient (0.5 mg Cu/kg) diets either with or without methionine supplementation (18 g/kg) for 49 days. Plasma caeruloplasmin (EC 1.16.3.1) and erythrocyte superoxide dismutase (EC 1.15.1.1, CuSOD) activities were measured in blood. Tissue Cu levels and the activities of cytochrome c oxidase (EC 1.9.3.1, CCO) and CuSOD were measured in the heart and liver. Hepatic activities of the sulfhydryl-sensitive enzymes, creatine kinase (EC 2.7.3.2), fumarase (EC 4.2.1.2) glutathione S-transferase (EC 2.5.1.18) and lipoamide dehydrogenase (EC 1.6.4.3) were also measured. Apart from cardiac CCO activity all of the measured indices of Cu status were found to be significantly (p less than 0.05) decreased in the methionine supplemented rats. Although fumarase activity was significantly (p less than 0.05) decreased in the methionine-supplemented animals compared with controls, the activities of the other sulfhydryl-sensitive enzymes were not significantly decreased. These results suggest that some of the toxic effects of excess dietary methionine may be mediated through interference with copper metabolism rather than through the previously postulated inhibition of sulfhydryl-sensitive enzymes by metabolites of methionine.
Asunto(s)
Cobre/farmacocinética , Complejo IV de Transporte de Electrones/metabolismo , Hígado/metabolismo , Metionina/farmacología , Miocardio/metabolismo , Animales , Cobre/análisis , Cobre/deficiencia , Creatina Quinasa/análisis , Creatina Quinasa/metabolismo , Dihidrolipoamida Deshidrogenasa/análisis , Dihidrolipoamida Deshidrogenasa/metabolismo , Complejo IV de Transporte de Electrones/análisis , Fumarato Hidratasa/análisis , Fumarato Hidratasa/metabolismo , Glutatión Transferasa/análisis , Glutatión Transferasa/metabolismo , Corazón/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Metionina/administración & dosificación , Metionina/toxicidad , Miocardio/enzimología , Estado Nutricional , Ratas , Ratas Endogámicas , Compuestos de SulfhidriloRESUMEN
Consumption of excess methionine by rats is known to cause membrane damage, liver enlargement and accumulation of iron in the spleen. In this study two groups (n = 5) of male, Wistar rats were pair-fed either a methionine supplemented (20.0 g/kg) or control (2.0 g/kg) diet for 7 weeks. Hepatic and erythrocyte copper-zinc superoxide dismutase activities were significantly reduced (P less than 0.05 and P less than 0.001 respectively) by methionine supplementation while the activities of catalase (P less than 0.01 and 0.05) and glutathione peroxidase (P less than 0.05) were significantly increased. Methionine supplementation also increased hepatic lipid peroxidation (P less than 0.01), as measured by the level of thiobarbituric acid reactive substances, and iron (P less than 0.001) concentrations. These changes are indicative of increased oxidative stress resulting from methionine toxicity.
Asunto(s)
Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Metionina/toxicidad , Animales , Catalasa/metabolismo , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Glutatión Peroxidasa/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratas , Ratas Endogámicas , Valores de Referencia , Superóxido Dismutasa/metabolismoRESUMEN
Three experiments were conducted to determine the histological and biochemical effects of toxic levels of dietary DL-methionine on broiler chicks fed an isolated soy-protein/cornstarch-purified diet containing 20% protein, 0.59% methionine, and 3,304 kilocalories of metabolizable energy per kilogram. An appropriate level of supplementary DL-methionine to use in toxicity studies was found to be 1.5%. It significantly depressed (P less than 0.01) gain in body weight, hematocrit, and hemoglobin concentration, increased (P less than 0.05) the level of iron in liver and spleen, caused pancreatic damage, and induced neurological changes. Unlike the retarded growth and increased iron levels in spleen and liver, the fall in hematocrit and hemoglobin values was independent of the reduction in feed intake caused by excess dietary methionine.
Asunto(s)
Pollos , Metionina/toxicidad , Enfermedades de las Aves de Corral/patología , Administración Oral , Animales , Peso Corporal , Cobre/sangre , Hematócrito , Hierro/metabolismo , Hígado/metabolismo , Metionina/administración & dosificación , Páncreas/patología , Enfermedades de las Aves de Corral/inducido químicamente , Enfermedades de las Aves de Corral/metabolismo , Bazo/metabolismoRESUMEN
Four Merino wethers were fed ad libitum on a roughage diet comprised of equal parts of chopped lucerne hay and oaten chaff. The sheep received continuous infusions of DL-methionine into the rumen; the daily dose increasing from 0 g (control treatment) up to 30 g in 3 g amounts at weekly intervals. Dry matter intake (DMI) fell below the control level when 24 g/day or more of the amino acid was infused, while plasma free methionine levels increase substantially when 30 g/day was given. There was no effect of DL-methionine supplementation on the bodyweight of the animals. However, when 30 g/day of DL-methionine was infused one animal died and the acute condition of 2 others necessitated their slaughter. Significant lesions included acute nephrosis and haemolytic anaemia, with milder changes in the liver and pancreas. This report indicates that sheep are unlikely to show the kind of chronic methionine toxicity seen in other species.
Asunto(s)
Metionina/toxicidad , Enfermedades de las Ovejas/inducido químicamente , Aminoácidos/sangre , Animales , Anorexia/inducido químicamente , Anorexia/veterinaria , Dieta , Intubación , Masculino , Metionina/administración & dosificación , Metionina/sangre , Rumen , Ovinos , EstereoisomerismoRESUMEN
The influence was experimentally studied of different lysine and methionine amounts in pig rations on gain, blood picture and some blood serum biochemical indexes. A 95 per cent gain was recorded when 0.14 per cent Bulgarian lysine was added to the basal ration as against the group whose ration was supplemented by 0.20 per cent crystal imported lysine. Groups administered toxic lysine and methionine doses showed minimal gain or none. Blood serum Ca amount nearly doubled for groups showing excess of dietary lysine while P and M levels for the same groups appreciably dropped. Blood sugar level went up in methionine toxicosis.