Response of Rats to Diets High in Methionine and Related Compounds

Cohen, Harold P.; Choitz, Harold C.; Berg, Clarence P.

doi:10.1093/jn/64.4.555

Cited by 48 publications

(22 citation statements)

References 18 publications

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“…Untreated homozygous mice lacking CBS have more severe liver damage than human patients, and this liver abnormality in mice is likely to contribute to their growth retardation and early death. Growth retardation has been observed in rats fed excessive methionine or homocystine (33), but it is not a characteristic of the human patients. Northern blot analysis of mRNA isolated from the livers of homozygous mutants showed no detectable transcripts for the Cbs gene (Fig: 3).…”

Section: Discussionmentioning

confidence: 99%

Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.

Watanabe

Osada

Aratani

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

535

518

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Studies by various investigators have indicated that elevated levels of plasma homocyst(e)ine are strongly associated with the occurrence of occlusive vascular diseases. With the eventual aim of determining whether or not elevated plasma homocyst(e)ine concentrations are directly causative of cardiovascular diseases, we have generated mice that are moderately and severely homocyst(e)inemic. Homologous recombination in mouse embryonic stem cells was used to inactivate the cystathionine 13-synthase [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22] gene. Homozygous mutants completely lacking cystathionine 13-synthase were born at the expected frequency from matings ofheterozygotes, but they suffered from severe growth retardation and a majority of them died within 5 weeks after birth. Histological examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets. Plasma homocyst(e)ine levels of the homozygotes were "40 times normal. These mice, therefore, represent a model for severe homocyst(e)inemia resulting from the complete lack of cystathionine 18-synthase. Heterozygous mutants have 509o reduction in cystathionine 8-synthase mRNA and enzyme activity in the liver and have twice normal plasma homocyst(e)ine levels. Thus, the heterozygous mutants are promising for studying the in vivo role of elevated levels of homocyst(e)ine in the etiology of cardiovascular diseases.Homocysteine is an intermediate amino acid in methionine metabolism and is either converted to cysteine by transsulfuration or methylated to form methionine. A decreased rate of metabolism through either of these pathways can lead to homocyst(e)inemia and homocystinuria.The of elevated homocyst(e)ine in the formation of thrombi or in the acceleration of atherogenesis is not well understood, various experiments suggest that homocysteine is a mediator of disease. For example, homocysteine damages cultured human venous and arterial endothelial cells (9, 10). Furthermore, DeGroot et al. (11) showed that cells grown from obligate heterozygotes for CBS deficiency were much more sensitive to methionine-mediated injury than were control cells. Other in vitro studies have demonstrated that homocysteine enhances autooxidation of low density lipoproteins (12), enhances biosynthesis of thromboxane (13), inhibits cell-surface thrombomodulin expression (14), promotes vascular smooth muscle cell growth (15), and enhances binding of lipoprotein(a) to fibrin (16). In vivo, long-term infusion of homocystine in baboons leads to endothelial desquamation, to an increase in platelet consumption, and to arterial lesions (17). However, there are also conflicting data indicating that an increased incidence of vascular diseases was not found in individuals heterozygous for homocystinuria (18,19). Determining whether elevated plasma homocyst(e)ine levels are causative of cardiovascular disease or are a consequence of the disease has been difficult because of the lack of an experimental animal mo...

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Section: Discussionmentioning

confidence: 99%

Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.

Watanabe

Osada

Aratani

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

535

518

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“…Other human studies using methionine have also reported no side effects (Kaji et al, 1987;Kies et al, 1975;Stegink et al, 1986). Nonetheless, specifically in the presence of a low protein diet or in developing animals as opposed to adults, high dose racemic or L-methionine can cause toxicities (Cohen et al, 1958;Klavins et al, 1963;Klavins and Johansen, 1965;Daniel and Waisman, 1969;Benevenga, 1974;Muramatsu et al, 1971). However those dosing levels are well above the dosing anticipated for human therapeutic levels for otoprotection.…”

Section: D-met Safety Factorsmentioning

confidence: 97%

Prevention of noise- and drug-induced hearing loss with d-methionine

et al. 2007

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“…Excess dietary Met has been shown to accelerate the turnover of hemoglobin by increasing the turnover and destruction of erythrocytes (7). This increase is likely to explain the splenic enlargement.…”

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confidence: 96%

Effect of Ingestion of Excess Methionine Diet on Aging of Erythrocytes in Mice.

Yasumoto

1992

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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SummaryAccelerated senescence prone mice and resistant mice (SAM-P/1 and SAM-R/ 1) were fed 10% casein diet or that supplemented with 2.5% methionine (Met) diet for 4 weeks. Erythrocytes withdrawn from animals of each group were separated by density gradient centri fugation into four fractions of different cell density, that is, different age of erythrocytes, and were analyzed for the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and the level of oxidized protein. Excess Met decreased the specific activity of GSH-Px in each fraction and the whole population of erythrocytes in SAM-P/1 but not in SAM-R/1. The changes in SOD activities were least significant among the erythrocyte fractions of every dietary group. The oxidized protein level in cell lysate increased with the increase of cell density in both strains of animals. These results were interpreted as indicating that excess Met had a positive effect on the erythrocytes senescence, and suggested that the activity of GSH-Px may be a useful enzymatic marker for the age of erythrocytes.

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Response of Rats to Diets High in Methionine and Related Compounds

Cited by 48 publications

References 18 publications

Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.

Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.

Prevention of noise- and drug-induced hearing loss with d-methionine

Effect of Ingestion of Excess Methionine Diet on Aging of Erythrocytes in Mice.

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