Methionine Toxicity in the Rat in Relation to Hepatic Accumulation of S-Adenosylmethionine: Prevention by Dietary Stimulation of the Hepatic Transsulfuration Pathway

doi:10.1006/abbi.1993.1083

Archives of Biochemistry and Biophysics

Volume 300, Issue 2, 1 February 1993, Pages 598-607

https://doi.org/10.1006/abbi.1993.1083 Get rights and content

Abstract

Rats were fed toxic levels of methionine with or with.. out 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.

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Cited by (47)

Postprandial plasma free amino acid profile and hepatic gene expression in juvenile barramundi (Lates calcarifer) is more responsive to feed consumption than to dietary methionine inclusion
2019, Aquaculture
The effects of dietary methionine (Met) supply on the postprandial pattern of plasma free amino acids and the differential expression of several genes associated with a number of sulfur amino acid and protein turnover pathways in the liver of juvenile barramundi (Lates calcarifer) was investigated. At the conclusion of a 49-day growth trial assessing the requirement for dietary Met, three treatments were selected (with deficient (DEF; 8.6 g kg⁻¹), adequate (ADQ; 14.9 g kg⁻¹) and excessive (EXC; 21.4 g kg⁻¹)) levels of dietary Met, based on their respective growth responses. A peak occurred in plasma free Met at 2 h post-feeding in fish fed the DEF and ADQ diets and at 4 h post-feeding in fish in the EXC treatment. Liver samples collected at these timepoints, as well as those taken as a pre-feeding control, were analyzed for expression of genes involved in Met turnover (CGL, MAT-1, MAT-2a) and taurine biosynthetic pathways (CSAD, ADO, CDO), target of rapamycin inhibition (Redd-1), the somatotropic axis (GHR-II, IGFI, IGF-II) and protein turnover pathways (MUL-1, ZFAND-5). Markers of sulfur amino acid turnover were more significantly affected by time after feeding than by dietary Met level, suggesting production of these enzymes may be primarily regulated by the consumption of feed or protein, rather than by the dietary composition. Further, metabolised Met appeared likely to have been directed through S-Adenosylmethionine (SAM) dependent pathways, rather than converted to Cys, which may have contributed to the observed growth response. Both genes influencing the conversion of Met to SAM appear to be active at this lifestage in barramundi. Previously described markers of proteolytic pathways appear to be conserved in this species and we have confirmed that ZFAND-5 is a reliable biomarker of this process in barramundi. A number of important genes were investigated for the first time in this species and shown to be nutritionally regulated.
Role of methionine on epigenetic modification of DNA methylation and gene expression in animals
2018, Animal Nutrition
Citation Excerpt :
Consequently, the hepatic ratio of SAM to SAH increased 8 times in both 1.3% and 2.3% methionine diets, respectively, compared with control diet (Rowling et al., 2002). Similarly, an 80% increase of the hepatic ratio of SAM to SAH was observed following the 7 times of SAM and 4 times of SAH increases caused by a 1.5% dietary methionine intake (Regina et al., 1993). The 1.7% methionine diet increased the serum SAM, SAH and ratio of SAM to SAH, especially the serum SAH concentration, which was elevated by 2.28 folds (Yang et al., 2015).
DNA methylation is one of the main epigenetic phenomena affecting gene expression. It is an important mechanism for the development of embryo, growth and health of animals. As a key nutritional factor limiting the synthesis of protein, methionine serves as the precursor of S-adenosylmethionine (SAM) in the hepatic one-carbon metabolism. The dietary fluctuation of methionine content can alter the levels of metabolic substrates in one-carbon metabolism, e.g., the SAM, S-adenosylhomocysteine (SAH), and change the expression of genes related to the growth and health of animals by DNA methylation reactions. The ratio of SAM to SAH is called ‘methylation index’ but it should be carefully explained because the complexity of methylation reaction. Alterations of methylation in a specific cytosine-guanine (CpG) site, rather than the whole promoter region, might be enough to change gene expression. Aberrant methionine cycle may provoke molecular changes of one-carbon metabolism that results in deregulation of cellular hemostasis and health problems. The importance of DNA methylation has been underscored but the mechanisms of methionine affecting DNA methylation are poorly understood. Nutritional epigenomics provides a promising insight into the targeting epigenetic changes in animals from a nutritional standpoint, which will deepen and expand our understanding of genes, molecules, tissues, and animals in which methionine alteration influences DNA methylation and gene expression.
Epigenetic regulation of pro-inflammatory cytokine genes in lipopolysaccharide -stimulated peripheral blood mononuclear cells from broilers
2017, Immunobiology
Citation Excerpt :
In this study we observed that DNMT1 and DNMT3a were down-regulated in a clear Met concentration-dependent manner. Those results may be induced by the increase in SAM and SAM: SAH ratio with Met addition (Regina et al., 1993; Rowling et al., 2002). Recent studies postulated that down-regulation of DNMT1 activity can mediate gene demethylation (Li et al., 2010; Tang et al., 2011).
Inflammatory response which can be mediated by inflammatory genes, can be induced by pathogenic microorganisms, be associated with enteric diseases and the loss of growth performance in broilers. The understanding of epigenetic regulation of inflammatory genes could help explain the response to infection of microorganisms and inhibit the reaction of inflammation in broilers. This study investigated the effect of histone acetylation by histone deacetylases (HDAC) inhibitors trichostain A (TSA) and DNA methylation by demethylation agent 5-Aza-2′-deoxycytidine (AZA) and methyl donor methionine (Met) and folic acid (FA) on the expression of pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) from healthy broilers. The results showed that the mRNA expression of IL-1β, IL-6 and TNF-α can be down-regulated by pre-treatment of TSA in LPS-stimulated broiler PBMC. The expression of pro-inflammatory cytokines related with the expression of HDAC7 and HDAC10 which can influence histone acetylation, and may also be affected by increasing the acetylation of non-histone proteins. The demethylation by AZA increased the expression of IL-6 and TNF-α in LPS-stimulated broiler PBMC. The addition of FA and Met decreased the expression of DNA methyltransferases (DNMT)1 and DNMT3a, while the Met also down-regulated the expression of IL-6 and TNF-α in LPS-stimulated cells. In addition, the Met administration increased the methylation of −191 CpG site (up-stream from transcription start site) of IL-6 and −419 CpG site of TNF-α. This study indicated that the expression of pro-inflammatory cytokines is regulated by protein acetylation. Demethylation also increased the expression of IL-6 and TNF-α, which can be regulated by Met through increasing the promoter methylation. These results may have implications for controlling inflammation by epigenetic regulation in broilers.
Determination of the lower and upper critical concentration of Methionine+Cystine in diets of juvenile turbot (Psetta maxima)
2016, Aquaculture
Citation Excerpt :
SAH is an intermediate product in the Met metabolism, a metabolite of S-Adenosylmethionine (SAM) and a precursor of l-Homocysteine (HCys) (Waterland, 2006). SAM, as well as SAH concentrations in the liver are positively correlated to the Met toxicity in rats (Regina et al., 1993). This accumulation in hepatic tissue can partly be explained by a dysfunction of the liver due to non-enzymatic methylation of macromolecules by SAM, as the most important donator of methyl groups in the organism (Kwasek et al., 2014; Regina et al., 1993).
In a 56 day lasting growth trial the lower and upper critical concentration of sulfur containing amino acids (Methionine, Met; Cystine, Cys) in diets for juvenile turbot (Psetta maxima) were determined. Nine different isonitrogenous diets (crude protein (CP) = 55.3% on dry matter (DM) basis) were fed in threefold repetition to juvenile turbots (mean live weight 25.8 g ± 3.0 s.d.) once daily until apparent satiation. Met + Cys concentrations of diet 1 to 7 ranged between 0.8% and 2.0% in DM, realized by 0.2% increments of l-Met supply. Cys concentration were steady at 0.3% of DM. Diets no. 8 and 9 contained 4.0 and 6.0% Met + Cys, respectively to cover the range of strong oversupply. A segmental linear regression model was applied to determine the lower and upper critical concentration of Met + Cys for relative growth (RG), relative feed intake (RFI), feed to gain ratio (FGR), protein efficiency ratio, metabolic retained CP and metabolic retained energy. The lower critical concentration for these parameters, except FGR, lies within a small range of 1.23–1.28% in diet DM (2.22–2.31% in CP). Whereas the range of the upper critical concentrations is larger (2.10–3.82% Met + Cys in diet DM; 3.80–6.91% in CP). The lower critical concentration derived for RG is 1.25% (± 0.02 s.e.) in diet DM (2.26% in CP) and for RFI 1.24% (± 0.03 s.e.) Met + Cys in diet DM (2.24% in CP). The upper critical concentration for RG is 2.68% (± 0.21 s.e.) (4.85% in CP) and 2.10% (± 0.41 s.e.) Met + Cys in diet DM (3.80% in CP) for RFI. The chemical body composition is significantly influenced by the Met + Cys concentration, especially at deficiencies. The apparent digestibility (organic matter, DM, CP, crude ash and energy) for 3 diets (no. 3, 5, 7) did not show significant differences, neither among the diets nor between the feces collection methods (stripping vs. dissection). At a strong oversupply of Met + Cys the concentration of hepatic S-Adenosylhomocysteine is negatively correlated to growth performance and can be used as one indicator of Met + Cys toxicity. Based on these values the amount of necessary Met supplementation in deficient diets or maximum inclusion rates of protein sources rich in Met + Cys can be derived for turbot.
High feed prices, especially for protein sources are a challenge for a sustainable aquaculture and fish feed industry. Therefore knowledge about amino acid requirement is necessary. This study determined the lower and upper critical concentrations of sulfur containing amino acids for turbot (Psetta maxima) at maximum performance. Based on these values optimum inclusion levels of protein sources can be derived.
Safety level evaluation of dietary 2-hydroxy-4-(methylthio) butanoic acid (HMTBa) for turbot Scophthalmus maximus based on growth performances, anti-oxidative responses, and liver and intestine conditions
2015, Aquaculture
A 56-day feeding trial was conducted to evaluate the safety level of 2-hydroxy-4-(methylthio) butanoic acid (HMTBa) as a dietary methionine source for turbot Scophthalmus maximus. Four isonitrogenous and isolipidic diets were formulated with graded levels of HMTBa (0%, 1%, 5% and 10%). These four experimental diets were named as H-0, H-1, H-5 and H-10, respectively. The effects of dietary HMTBa on growth performances, anti-oxidative responses, and liver and intestine conditions of turbot were analyzed. Results showed that the survival rate in H-10 treatment (95.83%) was significantly lower than that in H-1 (99.58%) (P < 0.05). The specific growth rate, feed efficiency, protein efficiency ratio and productive protein value were significantly higher in H-1 and H-5 treatments than those in H-0 and H-10 treatments (P < 0.05). The feed intake in H-5 and H-10 treatments was significantly higher than that in H-0 and H-1 treatments (P < 0.05). The activities of serum superoxide dismutase, serum glutathione peroxidase, liver glutathione peroxidase, liver catalase as well as the content of serum ascorbic acid and serum thiobarbituric acid reactive substance were significantly influenced by dietary HMTBa. Compared with those in H-0 and H-10 treatments, the significantly higher anti-oxidative abilities were observed in H-1 and H-5 treatments (P < 0.05). Deficient (H-0) or excessive (H-10) HMTBa in the diet had significantly negative effects on liver morphology. The same thing occurred on the intermediate and distal intestine structures. The significantly lower intestinal fold height and impaired integrity of intestinal structures were found in H-0 and H-10 treatments. The results in the present study indicated that the supplementation of HMTBa in the diet less than 5% is safe for turbot.
Total sulfur amino acid requirement and cystine replacement value for fingerling stinging catfish, Heteropneustes fossilis (Bloch)
2014, Aquaculture
Citation Excerpt :
By virtue of their particular structural or metabolic features, methionine is the most toxic of the amino acids and excessive intake results in impaired growth and toxicity in various animal models (De Mello, 1994; Harper et al., 1970). Its toxicity is thought to be due to the accumulation of S-adenosylmethionine (SAM) in the liver (Regina et al., 1993). Methionine is recognized as the most growth-depressing amino acid when fed in huge excess to farm livestock (Baker, 2006) and various fish species (Borlongan and Coloso, 1993; Jackson and Capper, 1982; Kaushik and Luquet, 1980; Mai et al., 2006; Murthy and Varghese, 1998; Zhou et al., 2006).
Heteropneustes fossilis is found in most of the Asian countries and has high consumer demand due to its recuperative and medicinal qualities. Being a lean fish with high iron content, it is recommended to people suffering from anemia and cardiac diseases. In view of the above, two 8-week feeding trials were conducted to determine total sulfur amino acid requirement (TSAA) and cystine replacement value for fingerling Singhi, H. fossilis. In experiment I, six casein gelatin based isonitrogenous (380 g kg^− 1 CP) and isocaloric (17.9 MJ kg^− 1 GE; 15.3 MJ kg^− 1 DE) amino acid test diets with graded levels of methionine (6.5, 8, 9.5, 11, 12.5, and 14 g kg^− 1 of the dry diet) were prepared. Cystine was maintained at 4 g kg^− 1 in all the diets. The diets were fed to quadruplicate groups of randomly assigned fingerlings (6.9 ± 0.1 g; 10.9 ± 0.2 cm) to apparent satiety twice daily at 28 °C water temperature in a flow-through system (1–1.5 L min^− 1). Based on the quadratic regression analysis at 95% maximum and minimum response of absolute weight gain (AWG g fish^− 1), feed conversion ratio (FCR), protein deposition efficiency (PDE%), energy deposition efficiency (EDE%), RNA:DNA ratio and methionine retention efficiency (MRE%), methionine requirements were found to range between 10.3 and 10.7 g kg^− 1 of dry diet, corresponding to 27.1–28.2 g kg^− 1 of the dietary protein. Hence, TSAA requirement was found to be 14.7 g kg^− 1 of the dry diet (10.7 g kg^− 1 methionine + 4 g kg^− 1 cystine). To find out the cystine replacement value for methionine, six diets with various ratios of methionine:cystine (90:10, 80:20, 70:30, 60:40, 50:50, and 40:60) on equimolar sulfur basis as per the TSAA requirement determined in experiment I (14.7 g kg^− 1) were prepared and fed to fingerling H. fossilis (7.2 ± 0.2 g; 11.3 ± 0.1 cm) under identical laboratory conditions. The quadratic regression analysis of AWG g fish^− 1, FCR, PDE%, EDE%, RNA:DNA ratio and MRE% at 95% maximum and minimum quadratic response projected that cystine could replace from 39.6 to 40.2% of methionine requirement on an equimolar sulfur basis without hampering growth. On the basis of the above results, the total sulfur amino acid requirement of the H. fossilis is recommended to be 14.7 g kg^− 1 dry diet (7.1 g kg^− 1 methionine + 7.6 g kg^− 1 cystine) of which 39.9% was spared by cystine.

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Regular ArticleMethionine Toxicity in the Rat in Relation to Hepatic Accumulation of S-Adenosylmethionine: Prevention by Dietary Stimulation of the Hepatic Transsulfuration Pathway

Abstract

Regular Article
Methionine Toxicity in the Rat in Relation to Hepatic Accumulation of S-Adenosylmethionine: Prevention by Dietary Stimulation of the Hepatic Transsulfuration Pathway