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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #204889
Title: Copper deficiency decreases plasma homocysteine in rats

Author
item Uthus, Eric
item Reeves, Phillip
item Saari, Jack

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/28/2007
Publication Date: 6/1/2007
Citation: Uthus, E.O., Reeves, P.G., Saari, J.T. 2007. Copper deficiency decreases plasma homocysteine in rats. Journal of Nutrition. 137:1370-1374.

Interpretive Summary: Copper deficiency has long been recognized as detrimental for the cardiovascular system. Also, increased blood homocysteine concentrations are linked to increased cardiovascular disease in humans. A previous study by other researchers showed that copper deficient rats had increased blood homocysteine. The purpose of this study was to determine the effects in rats of copper deficiency on key aspects of homocysteine metabolism. This would help us determine whether changes in homocysteine metabolism may explain some of the effects of copper deficiency on the cardiovascular system. Contrary to the previous study, we found in two separate experiments that copper deficiency results in decreased, not increased, homocysteine. We also confirmed earlier findings that blood glutathione (which can be derived from homocysteine and is an important compound in protection against oxidative injury) is increased by copper deficiency. Our work also showed that several enzymes important for homocysteine and glutathione metabolism are altered by copper deficiency. The alterations in these enzymes, caused by copper deficiency, allow for more homocysteine to be shunted to glutathione synthesis. The net effect is decreased homocysteine and increased glutathione content in blood of copper deficient rats. These results suggest that the detrimental effects of copper deficiency on the cardiovascular system are most likely not the result of copper’s effect on homocysteine metabolism.

Technical Abstract: The purpose of this study was to determine the effects of copper deficiency on key aspects of homocysteine metabolism that involve methionine recycling and transsulfuration. Male weanling Sprague-Dawley rats were fed AIN-93-G-based diets containing <1 or approximately 6 mg Cu/kg. After 6 wk (experiment 1) and 4 wk (experiment 2), we found that plasma homocysteine was significantly decreased and plasma glutathione significantly increased in rats fed the low-Cu diet. Real-time RT PCR was used to determine the expression of the subunits of glutamate-cysteine ligase (Gcl) in liver that catalyzes the rate-limiting step in glutathione biosynthesis. The expression of Gclc, the catalytic subunit of Gcl, was up-regulated by Cu deficiency; Gclm, the modifier subunit, was not affected. Hepatic betaine-homocysteine methyltransferase, which catalyzes one of the two ways that homocysteine can be remethylated to methionine, was down-regulated by Cu deficiency. Because Cu deficiency results in up-regulation of Gclc and an increase in the biosynthesis of glutathione, it is plausible that the net flux of homocysteine through the transsulfuration pathway is increased. Furthermore, if Bhmt is down-regulated, less homocysteine is available for remethylation (methionoine recycling) and more is then available to irreversibly enter the transsulfuration pathway where it is lost. The net effect of increased Gclc and decreased Bhmt would be a decrease in homocysteine as a result of Cu deficiency.