A 4-Week Toxicity Study of Methionine in Male Rats

Abstract

To examine 4-week toxicity of l-methionine (methionine), 5-week-old Fisher strain male rats were fed on diets containing 0, 0.1, 0.3, 0.9, 2.7 (w/w) of added methionine. Although no deaths were recorded, the highest dose of methionine (2.7% [w/w] of diet) reduced food intake and significantly suppressed growth rate. Growth suppression was characterized by an increase in hemolysis, splenic, and hepatic accumulation of hemosiderin, hemolytic anemia, and promotion of hematopoiesis. Other changes observed in the highest methionine intake group were a decrease in white blood cell count, thymus atrophy, and histological abnormalities in the adrenal gland and testis. Small, but significant, growth suppression, accompanied by some minor changes in plasma biochemical parameters, was also seen in rats fed on a test diet containing 0.9% (w/w) of additional methionine. Thus, no-observed-adverse-effect-level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of diet-added methionine were determined at 0.3% and 0.9% (w/w), corresponding to 236 and 705 mg/kg/d body weight, respectively. Since the basal diet contained protein-bound methionine at 0.5% (w/w), NOAEL and LOAEL of total dietary methionine were estimated at 0.8% and 1.4% (w/w) of diet.

The Effects of Subchronic Methionine Overload Administered Alone or Simultaneously with L-cysteine or N-acetyl-L-cysteine on Body Weight, Homocysteine Levels and Biochemical Parameters in the Blood of Male Wistar Rats

“…The hyperhomocysteinemia induced by methionine administration leads to increased production of free radicals and inflammation markers in macrophages of the mouse peritoneum (5). An in vitro and in vivo study on rats showed the alteration of oxidative stress parameters after the methionine administration (6), and hemosiderin accumulated in rat hepatocytes after a four-week methionine treatment (7). The occurrence of hyperhomocysteinemia was also reported in a population of patients with inflammatory bowel disease after an oral overload with methionine (8).…”

“…limiting the production of reactive oxygen species (6,7). Methionine removes metabolic waste products from the liver and can thus decrease the risk of hepatic and arterial steatosis.…”

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

“…l ‐Met being an essential amino acid, its intake needs to be regulated and its systemic levels should be optimized so that it can maintain normal body homeostasis. Recent studies show that methionine intake up to 91 mg kg –1 body of weight in humans and 705 mg kg –1 body of weight per day in an animal is well tolerated to sustain a healthy life . In view of this, we designed in vivo study of l ‐Met‐S in diabetic animals and selected the dose of l ‐Met for our animal study.…”

“…l ‐Met along with other methyl donors has been shown to improve glucose tolerance and insulin sensitivity in offspring of high‐fat diet (HFD) fed dams, reduce fatty liver in high fat‐sucrose diet fed rats via alteration in DNA methylation, and activate AMPK and prevent the Non‐alcoholic fatty liver disease (NAFLD) in obese mice . However, there is a risk of an increase in homocysteine level (a risk factor for cardiovascular disease) and decreased body weight with increased intake of l ‐Met . There are reports suggesting that methionine restriction can improve insulin sensitivity, glucose homeostasis, oxidative stress, lipid metabolism, and longevity .…”

“…[30] However, there is a risk of an increase in homocysteine level (a risk factor for cardiovascular disease) and decreased body weight with increased intake of l-Met. [25,31,32] There are reports suggesting that methionine restriction can improve insulin sensitivity, glucose homeostasis, oxidative stress, lipid metabolism, and longevity. [33][34][35][36][37] Contrary to the beneficial effects of methionine restriction, other reports also showed that long-term methionine restriction in young animals alters bone structure, stunts growth, increases homocysteine level, hepatocellular injury, oxidative stress, inflammation, and methionine deficient diet increases the risk of developing nonalcoholic steatohepatitis.…”