Methionine Ingestion Research Articles

A short-term intervention of ingesting iron along with methionine and threonine leads to a higher hemoglobin level than that with iron alone in young healthy women: a randomized, double-blind, parallel-group, comparative study.

Enhancing iron absorption and utilization is important for amelioration iron status faster and thereby, for improving quality of life. Dietary protein and amino acids, including methionine and threonine, have been reported to facilitate the absorption and utilization of dietary iron. Here, we investigated the effect of combined ingestion of methionine, threonine, and iron on the improvement of iron status during a short-term intervention, by comparing that with iron ingestion alone in healthy young women. This was a randomized, double-blind, parallel-group, comparative study with 45 participants (aged 20-39) randomly assigned to three groups (n = 15 each): one group was administered 200mg methionine, 400mg threonine, and 6mg iron once daily (FEMT); another ingested 6mg iron alone (FE); and the third group ingested a placebo (PCG). Blood samples and dietary nutrient data were collected before the intervention (week 0) and after 2, 4, and 6weeks. Serum iron, hemoglobin, transferrin, and ferritin levels were measured. Blood hemoglobin levels were significantly higher in the FEMT than in the FE group (P < 0.05) at week 4. Serum iron, transferrin, and ferritin levels were not changed across groups. In addition, our analyses showed that the observed increase in hemoglobin levels was affected by the intervention rather than changes in dietary nutrient intake. Ingestion of methionine and threonine with low doses of iron leads to a higher hemoglobin levels than that with iron alone in a short period of 4weeks. University Hospital Medical Information Network Clinical Trial Registry (UMIN000046621).

Impact of Methyl-Donor Micronutrient Supplementation on DNA Methylation Patterns: A Systematic Review and Meta-Analysis of in vitro, Animal, and Human Studies

Background: DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation levels, and altered ingestion of folate, choline, betaine, B vitamins and methionine may impact genes both globally and at the level of promoter regions. Despite this, the role of methyl-donor micronutrient supplementation on DNA methylation profiles is currently unclear. Objectives: The aims of this systematic review and meta-analysis were to identify and synthesize the evidence about methyl-donor nutrient supplementation on DNA methylation. Methods: A systematic literature search was performed in Medline, Embase, Scopus, and Web of Science databases with a combination of terms related to DNA methylation assessment, supplementation, and methyl-donor nutrients. Studies (in vitro, animal models, or human clinical trials) were included if DNA methylation levels after any kind of methyl-donor micronutrient supplementation or treatment was investigated. Studies were assessed for bias using Revised Cochrane risk-of-bias tool for randomized trials, risk-of-bias in Non-randomized Studies of Interventions or Systematic Review Centre for Laboratory Animal Experimentation tools. Data were extracted from studies measuring DNA methylation levels in any sample or tissue, following any kind of methyl-donor micronutrient supplementation or treatment. Separate random-effects meta-analyses were performed for animal model studies and human clinical trials that examined the effects of folic acid supplementation on DNA methylation. Results: Fifty-seven studies were included in this systematic review: 18 human clinical trials, 35 in animal model, and 4 in vitro studies. Concerning overall risk of bias, most of the studies were classified as “high risk” or “some concerns.” Meta-analysis with meta-regression from studies in animal models showed that folic acid dose significantly affected DNA methylation and that high and very high doses showed increases in DNA methylation when compared to low doses. However, meta-analysis of human clinical trials showed that folic acid supplementation did not promote significant changes in DNA methylation when compared to placebo. Conclusion: Folic acid supplementation may change global DNA methylation levels in animals supplemented with high, as compared to low, doses. Heterogeneity in studies and supplementation protocols make it difficult to establish clinical recommendations. However, these effects, even if small, might be of clinical importance in the management of patients with diseases related to DNA hypomethylation.

Pilot Study Assessing Tolerability and Metabolic Effects of Metformin in Patients With Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline TP53 pathogenic variants has not been documented. This study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline TP53 variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor-1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO2 after ingestion of 13C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided. We enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean 13C exhalation was statistically significantly suppressed by metformin (P = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered (P = .02). Lipid metabolites and branched-chain amino acids accumulated. Metformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.

Different nutrient intake and prevalence of gastrointestinal comorbidities in women with endometriosis.

Even though endometriosis presents one of the most common gynaecological diseases, the pathogenesis is insufficiently studied. Besides immunologic, inflammatory or oxidative processes, recent studies also suggest an influence of nutrition on disease onset and progression. Because data about the actual nutrient intake of endometriosis patients are scarce, we aimed to examine the actual nutrient intake and potential influencing factors in these women. A total of 156 women with endometriosis (EM) and 52 age-matched controls were included in this retrospective case-control study. All women filled in a validated food frequency questionnaire to acquire the nutrient intake of the past 12 months and a disease-related questionnaire for the determination of disease status, clinical symptoms and comorbidities. Patients with endometriosis suffered significantly more from diet-related comorbidities like food intolerances (25.6% versus 7.7%; P = 0.009) and allergies (57% versus 31%; P < 0.001) compared to controls. Also gastrointestinal symptoms, including constipation, flatulence, pyrosis, diarrhea or frequent defecation, were higher in the EM group (77% versus 29%; P < 0.001). The nutrient intake of patients with endometriosis differed significantly compared to controls with a significantly lower ingestion of organic acids (P = 0.006), maltose (P = 0.0.16), glycogen (P = 0.035), tetradecenoic acid (P = 0.041), methionine (P = 0.046), lysine (P = 0.048), threonine (P = 0.046) and histidine (P = 0.049). The total intake of animal proteins was significantly lower in the EM group compared to the controls (P = 0.047). EM patients showed a decreased intake of vitamin C (P = 0.031), vitamin B12 (P = 0.008) and magnesium (P = 0.043) compared to controls. This study confirms a high association of endometriosis and gastrointestinal disorders accompanied by an altered nutrient intake. A dietary intervention by a professional nutritionist may help to reduce disease burden in the affected women.

Retrospective evaluation of methionine intoxication associated with urinary acidifying products in dogs: 1,525 cases (2001-2012).

To describe the signalment, clinical findings, timing of signs, outcome, and prognosis in a population of dogs exposed to methionine through the ingestion of urine acidifying products. Retrospective observational study from January 1, 2001 to December 31, 2012. Animal Poison Control Center. A total of 1,197 case calls yielding 1,525 dogs identified with presumed methionine ingestion. None. Records of dogs with presumptive methionine ingestion were reviewed from the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center database. Ingested methionine doses ranged from 3.9 mg/kg to 23,462 mg/kg. Clinical signs developed in 47% of dogs. The most common clinical signs were gastrointestinal (GI) and neurologic. The mean onset of GI signs was 2.8 hours following ingestion. The mean onset of neurologic signs was 6.8 hours following ingestion. GI signs were identified with ingested doses ≥22.5 mg/kg. Vomiting was the most common GI sign. Neurologic signs were identified with ingested doses ≥94.6 mg/kg. Ataxia was the most common neurologic sign. Resolution of clinical signs occurred within 48 hours of ingestion, and no fatalities were reported. Prognosis for dogs with methionine intoxication is excellent. Vomiting and ataxia were the most common clinical signs associated with methionine toxicosis.

The first international mini-symposium on methionine restriction and lifespan.

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan (Orentreich et al., 1993). Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases (Richie et al., 1994; Miller et al., 2005; Ables et al., 2012; Sanchez-Roman and Barja, 2013). We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed. The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies (Figure 3).

Regulation of longevity and oxidative stress by nutritional interventions: Role of methionine restriction

Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seems to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) is enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction changes these parameters. In addition, old rats also conserve the capacity to respond to 7weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA.

FOLIC ACID REDUCES ADHESION MOLECULES VCAM-1 EXPRESSION ON ENDOTHELIUM IN RATS WITH HYPERHOMOCYSTEINEMIA

ObjectivesTo investigate the effects of folic acid supplementation on the expression of adhesion molecules VCAM·1 in aortic endothelium of rats with hyperhomocys teinemia (HHCY) induced by ingestion of excess methionine...

Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria

It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (MetR) also increases, like DR, rodent maximum longevity. However, it is not known if old rats maintain the capacity to lower mitROS generation and oxidative stress in response to MetR similarly to young immature animals, and whether MetR implemented at old age can reverse aging-related variations in oxidative stress. In this investigation the effects of aging and 7 weeks of MetR were investigated in liver mitochondria of Wistar rats. MetR implemented at old age decreased mitROS generation, percent free radical leak at the respiratory chain and mtDNA oxidative damage without changing oxygen consumption. Protein oxidation, lipoxidation and glycoxidation increased with age, and MetR in old rats partially or totally reversed these age-related increases. Aging increased the amount of SIRT1, and MetR decreased SIRT1 and TFAM and increased complex IV. No changes were observed in the protein amounts of PGC1, Nrf2, MnSOD, AIF, complexes I, II and III, and in the extent of genomic DNA methylation. In conclusion, treating old rats with isocaloric short-term MetR lowers mitROS production and free radical leak and oxidative damage to mtDNA, and reverses aging-related increases in protein modification. Aged rats maintain the capacity to lower mitochondrial ROS generation and oxidative stress in response to a short-term exposure to restriction of a single dietary substance: methionine.

The effects of dietary supplementation of methionine on genomic stability and p53 gene promoter methylation in rats

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.

La restricción de metionina en la dieta disminuye el estrés oxidativo en mitocondrias de corazón

Introduction caloric restriction (CR) decreases the production of mitochondrial reactive oxygen species (MitROS) and oxidative damage to mitochondrial DNA (mtDNA) and increases maximum longevity, but the mechanisms responsible for these effects are unknown. We have found that protein restriction (PR) also produces these changes. Various findings link methionine to ageing; moreover, like CR, methionine restriction (MetR) increases maximum longevity. We hypothesized that MetR is responsible for the decrease in MitROS generation and oxidative stress that takes place in PR and CR. Material and methods male Wistar rats were subjected to methionine restriction or fed ad libitum for 7 weeks. Functional heart mitochondria were isolated by centrifugation. Mitochondrial respiration was measured by polarography with a Clark electrode and MitROS production was assayed by fluorometry. Oxidative damage to mtDNA (8-oxodG) was measured by HPLC with electrochemical detection. Results MetR decreased MitROS generation at complex I, did not change mitochondrial oxygen consumption, and decreased 8-oxodG levels in mtDNA. Conclusions the changes induced by MetR in the rate of MitROS generation and 8-oxodG are similar to those previously observed in CR and PR. This suggests that the reduction in methionine ingestion is responsible for the decrease in mitROS production and oxidative stress and part of the decrease in the rate of ageing that occurs during caloric restriction. Protein (and methionine) restriction provide the first possibility of an intervention that could be applied to western populations, including the Spanish population. This type of intervention could potentially delay the rate of ageing by approximately 20% and could decrease the incidence of all degenerative diseases without the need to reduce dietary caloric intake.

Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins

Previous studies have consistently shown that caloric restriction (CR) decreases mitochondrial reactive oxygen species (ROS) (mitROS) generation and oxidative damage to mtDNA and mitochondrial proteins, and increases maximum longevity, although the mechanisms responsible for this are unknown. We recently found that protein restriction (PR) also produces these changes independent of energy restriction. Various facts link methionine to aging, and methionine restriction (MetR) without energy restriction increases, like CR, maximum longevity. We have thus hypothesized that MetR is responsible for the decrease in mitROS generation and oxidative stress in PR and CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their longevity. We have found, for the first time, that MetR profoundly decreases mitROS production, decreases oxidative damage to mtDNA, lowers membrane unsaturation, and decreases all five markers of protein oxidation measured in rat heart and liver mitochondria. The concentration of complexes I and IV also decreases in MetR. The decrease in mitROS generation occurs in complexes I and III in liver and in complex I in heart mitochondria, and is due to an increase in efficiency of the respiratory chain in avoiding electron leak to oxygen. These changes are strikingly similar to those observed in CR and PR, suggesting that the decrease in methionine ingestion is responsible for the decrease in mitochondrial ROS production and oxidative stress, and possibly part of the decrease in aging rate, occurring during caloric restriction.

Iron sucrose augments homocysteine-induced endothelial dysfunction in normal subjects

Intravenous iron is commonly used in conjunction with erythropoietic agents to treat anemia in patients with chronic kidney disease. Iron has been proposed to promote oxidative stress and endothelial dysfunction in vascular tissues. We studied the acute effects of intravenous iron sucrose on homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. In all, 40 healthy subjects received intravenous iron sucrose 100 mg or placebo over 30 min immediately before ingestion of 100 mg/kg of oral methionine in a double-blind, randomized study. Flow- and nitroglycerin-mediated dilation in the brachial artery, serum markers of iron stores, and homocysteine and nitrotyrosine levels were measured before and after study drug administration. Intravenous iron significantly increased transferrin saturation and non-transferrin-bound iron (NTBI) when compared with placebo. Flow-mediated dilation significantly decreased from baseline 1 h after administration of iron sucrose when compared with placebo (from 6.66+/-0.47 to 1.93+/-0.35% after iron sucrose vs from 6.00+/-0.40 to 5.61+/-0.46% after placebo, P<0.001), but did not differ between groups at 4 h (1.10+/-0.39 vs 1.33+/-0.51%). Nitroglycerin-mediated vasodilation, and homocysteine and 3-nitrotyrosine levels did not differ after administration of iron sucrose and placebo. Intravenous administration of iron sucrose in the setting of transient hyperhomocysteinemia induced by methionine ingestion significantly increased transferrin saturation and plasma levels of NTBI and significantly attenuated flow-mediated dilation in the brachial artery when compared with placebo. This potential mechanistic link between intravenous iron and endothelial dysfunction warrants further study of cardiovascular effects of intravenous iron in anemic chronic kidney disease populations.

Changes in pulmonary vascular function after acute methionine loading in normal men.

Elevated blood levels of Hcy (homocysteine) are associated with endothelial dysfunction in the systemic and coronary arterial beds. We wished to know if similar changes could be detected in the pulmonary circulation, using non-invasive tests. We studied ten normal young men aged 23-31 years, in whom acute hyperhomocysteinaemia was induced by oral ingestion of methionine. Cardiopulmonary exercise testing [including measurement of exhaled breath NO (nitric oxide)] was performed on two occasions, with and without methionine loading. In addition, blood samples for vWf (von Willebrand factor) and factor VIIIc were taken as markers of endothelial function. After oral methionine, plasma Hcy increased from 11.8 +/- 3.1 to 31.2 +/- 10.3 micromol/l (values are means +/- S.D.; P < 0.0001), whereas there was no increase after placebo. After exercise there was an increase in V(NO) (NO production) and circulating plasma levels of vWf and factor VIIIc, but these were similar in the two tests. Exercise time, HR (heart rate) and BP (blood pressure) responses and P V(O2) (peak achieved O2 uptake) were also similar in the two tests. V(E) (expiratory minute ventilation)/ V(CO2) (CO2 production) was similar in the two groups at rest (methionine, 31.9 +/- 3.9; placebo, 30.5 +/- 3.9; P = 0.11), but increased during exercise after methionine (at peak, 32.2 +/- 4.6 compared with 29.9 +/- 2.8; P = 0.016). P(ETCO2) (end-tidal partial pressure of CO2) was also similar in the two groups at rest (35.1 +/- 2.9 compared with 36.8 +/- 3.2; P = 0.11), but decreased throughout the methionine test (peak 34.1 +/- 4.4 compared with 36.7 +/- 3.5; P = 0.006). V(E) vs V(CO2) slope also increased in the methionine test (25.2 +/- 2.4 compared with 22.8 +/- 2.3; P = 0.003). In conclusion, small, but consistent and significant, changes in respiratory gas exchange were seen after methionine loading, compatible with a V / Q (ventilation/perfusion) mismatch due to pulmonary vascular endothelial dysfunction.

Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P</=0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P=0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.

Effects of acute methionine loading and vitamin Con endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0±0.1 to 4.7±0.4 ng/ml; P &amp;lt; 0.001) and activity (from 1.2±0.2 to 4.2±0.4 i.u./ml; P &amp;lt; 0.001), which were augmented during acute methionine loading (4.7±0.4 to 5.6±0.5 ng/ml and 4.2±0.4 to 5.5±0.9 i.u./ml respectively; P⩽0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P = 0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.

Free methionine supplementation limits alcohol-induced liver damage in rats.

Alcohol feeding to rats that were submitted to a jejunoileal bypass operation has been shown to result in liver damage being comparable with alcohol-induced liver disease in man. In the present study, a striking effect of free methionine consumption on histological liver injury, triglyceride accumulation, and energy-rich nucleoside content in the liver of rats with a jejunoileal bypass is demonstrated. The animals obtained 0, 30, and 120 mg of methionine in the control group and 0, 30, 120, and 240 mg in the alcohol-fed group per day and per kilogram of body weight for 12 weeks. Methionine was found to strongly improve the alcohol-induced histological changes in the liver. Triglyceride content of the liver was found to decrease in a dose-dependent manner with increasing methionine ingestion (from 255 +/- 20.7 to 49.7 +/- 6.1 micromol/g of protein in the control group and from 233 +/- 17.3 to 42.1 +/- 7.2 micromol/g of protein in the alcohol group). Hepatic adenosine triphosphate content increased significantly with higher methionine consumption (13.5 +/- 0.8 vs. 26.9 +/- 2.8 micromol/g of protein in the control group and 11.9 +/- 1.4 vs. 20.5 +/- 2.5 micromol/g of protein in the alcohol group), whereas no differences were found in the protein and DNA content of the liver. These results underscore the impairment of the transmethylation/transsulfuration pathway in the development of alcohol-induced liver diseases.

Vitamin E prevents the elevation of thiobarbituric acid-reactive substances but not hemolytic anemia in rats fed excess methionine

Supplementing an 8% casein (8C) diet with 3% methionine (8C3M) resulted in a 13% reduction in hemoglobin in rats compared with control (8C). The NaCl concentration which caused 50% hemolysis of erythrocytes incubated at 37°C for 24 hr was 0.85% for 8C and 1.05% for 8C3M. The plasma levels of thiobarbituric acid-reactive substances (TBARS) and Cu, Zn-superoxide dismutase (SOD) activity of erythrocytes in the 8C3M group were 15% higher and 35% lower than those of the 8C group, respectively. Supplementation with vitamin E to 8C3M (all-rac-α-tocopheryl acetate, 4,240 μmol/kg of diet, 10 times the amount in other diets) prevented the elevation in plasma TBARS and the decrease in SOD activity of erythrocytes but did not affect the development of anemia. Alteration of the cytoskeletal protein composition of erythrocyte membranes in the 8C3M group was observed. Those hematological alterations caused by excess methionine ingestion were prevented by the addition of 3% glycine to the 8C3M diet.

Maternal hyperhomocysteinemia: A risk factor for neural-tube defects?

The maternal vitamin status, especially of folate, is involved in the pathogenesis of neural-tube defects (NTDs). Maternal folate administration can prevent these malformations. The precise metabolic mechanism of the beneficial effect of folate is unclear. In this study we focus on homocysteine accumulation, which may derive from abnormalities of metabolism of folate, vitamin B 12, and vitamin B 6. We studied nonpregnant women, 41 of whom had given birth to infants with NTDs and 50 control women who previously had normal offspring. The determinations included the plasma total homocysteine both in the fasting state and 6 hours after the ingestion of a methionine load. In addition, we measured the fasting blood levels of folate, vitamin B 12, and vitamin B 6. The mean values for both basal homocysteine and homocysteine following a methionine load were significantly increased in the group of women who previously had infants with NTDs. In nine of these subjects and two controls, the values after methionine ingestion exceeded the mean control by more than 2 standard deviations. Cystathionine synthase levels in skin fibroblasts derived from these methionine-intolerant women were within the normal range. Our findings suggest a disorder in the remethylation of homocysteine to methionine due to an acquired (ie, nutritional) or inherited derangement of folate or vitamin B 12 metabolism. Increased homocysteine levels can be normalized by administration of vitamin B 6 or folate. Therefore, we suggest that the prevention of NTDs by periconceptional folate administration may effectively correct a mild to moderate hyperhomocysteinemia.

Modulation of the secretion of potassium by accompanying anions in humans

In animals, secretion of potassium (K) in the cortical collecting duct (CCD) is modulated by the properties of the accompanying anion. In humans, results are inconclusive as previous studies have not differentiated between a kaliuresis due to a rise in the concentration of K from one due to an increase in the volume of urine. Our purpose was to study the effects of chloride (Cl) and bicarbonate on the secretion of K in the CCD in humans using the transtubular K concentration gradient (TTKG), a semi-quantitative index of secretion of K in the terminal CCD. After control blood and urine samples were obtained, all subjects ingested 0.2 mg fludrocortisone to ensure that mineralocorticoids were not limiting the secretion of K. The anionic composition of the urine was varied using three protocols: Normal subjects (N = 11) ingested cystine and methionine to induce sulfaturia; nine subjects with a contracted ECF volume (to lower the concentration of Cl in the urine) were also studied during sulfaturia following the ingestion of cystine and methionine; 13 normovolemic subjects were studied during bicarbonaturia following the ingestion of acetazolamide. When the concentration of Cl in the urine was greater than 15 mmol/liter, sulfate had no effect on the TTKG. With lower concentrations of Cl in the urine, the TTKG rose 1.5-fold. The TTKG rose 1.8-fold in the presence of bicarbonaturia despite concentrations of Cl in the urine that were greater than 15 mmol/liter, suggesting that bicarbonate has additional effects on this K secretory process. At comparable concentrations of sulfate and bicarbonate in the urine, the TTKG was increased only with bicarbonaturia.(ABSTRACT TRUNCATED AT 250 WORDS)