Screening of Toxicity Biomarkers for Methionine Excess in Rats

Abstract

Although many animal studies have reported that dietary excess of methionine causes toxic changes including growth suppression and hemolytic anemia, the biochemical mechanism and biomarkers for methionine toxicity have not been well elucidated. The present study aimed to identify toxicity biomarkers from plasma metabolites in rats fed excessive methionine. Young growing rats were fed graded doses of additional methionine for 2 wk. Cluster analysis of multivariate correlations was performed on the physiological and toxicity variables with plasma metabolites detected by GC/MS, amino acid analyzer, and thiol-specific analysis. Indicative variables for hemolysis such as splenic nonheme iron content and plasma bilirubin were grouped in the same cluster as many methionine metabolites. Homocysteine and some undefined metabolites in this cluster were found to be strong discriminators between nontoxic and toxic levels of methionine intake. Product-to-precursor ratios of each methionine metabolite demonstrated that excessive methionine intake caused a marked decrease only in the ratio of cystathionine to homocysteine, suggesting that metabolism from homocysteine to cystathionine would be rate limiting in the disposal of excessive methionine. Collectively from these results, homocysteine appeared to be the most plausible biomarker to assess methionine excess as a surrogate marker both for toxicity and for setting a metabolic upper limit.

Experimental Hyperhomocysteinemia Reduces Bone Quality in Rats

“…The study had several limitations. Although the mean HCY concentration in the methionine group was similar to that reported by others (17 ) (27.3 vs 25.3 mol/L), excessive methionine supplementation in rats is known to have toxic effects, such as hemolytic anemia and growth suppression (18 ). HCY appears to be among the most plausible explanations for these toxic effects (18 ), but it is possible that methionine-induced effects might reflect systemic toxicity.…”

“…Although the mean HCY concentration in the methionine group was similar to that reported by others (17 ) (27.3 vs 25.3 mol/L), excessive methionine supplementation in rats is known to have toxic effects, such as hemolytic anemia and growth suppression (18 ). HCY appears to be among the most plausible explanations for these toxic effects (18 ), but it is possible that methionine-induced effects might reflect systemic toxicity. We thus substantiated our observations by another, biochemically different model of HHCY consisting of a homocystine-enriched diet, and achieved mean HCY concentrations similar to those reported by Joseph et al (19 ), who used a 9 g/kg homocystine diet.…”

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

“…KMTB is then oxidatively decarboxylated to 3-methylthiopropionate (MTP) through an irreversible reaction catalyzed by the branched chain 2-oxo acid dehydrogenase complex (BCKDC) (15). MTP is further metabolized to the gaseous methanethiol (16), which has been reported to then be broken down into simpler molecules, including hydrogen sulfide, dimethyl sulfide, and formic acid, with the end products being carbon dioxide and sulfur dioxide (17,18). Although initial reports on methionine transamination suggested that it provides a route for the degradation and clearance of methionine (19), more recently researchers have claimed that transsulfuration serves as the major pathway for the detoxification of excessive methionine (20).…”

Hyperhomocysteinemia Lead to Transmural Inflammation of Colon and Increase Severity of Disease in Acetic Acid-Induced Colitis in Rat

“…On the other hand, diet supplementation with low doses of methionine (0.2%, 0.3%, 0.4% feed weight) favored increased feed intake and animal growth [18][19][20][21].…”