Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia.

Abstract

Elevated plasma levels of homocysteine are a risk factor for cardiovascular diseases, neural tube defects, and Alzheimer's disease. The transsulfuration pathway converts homocysteine to cysteine, and approximately 50% of the cysteine in glutathione is derived from homocysteine in human liver cells, which suggests the hypothesis that defects in the transsulfuration pathway perturb redox homeostasis. To test this hypothesis, we examined a murine model for hyperhomocysteinemia in which the gene encoding the first enzyme in the transsulfuration pathway, cystathionine beta-synthase (CBS), has been disrupted. Limited metabolite profiling and CBS expression studies in liver, kidney, and brain reveal tissue-specific differences in the response to Cbs disruption. Homozygous disruption of Cbs lowered cysteine concentration in all three organs. Glutathione concentration was diminished in liver and brain, thus affecting the redox buffering capacity in these organs, whereas the approximately twofold higher glutathione synthesis capacity in kidney helped preserve the glutathione pool size despite loss of the transsulfuration pathway in this organ. In contrast, disruption of a single Cbs allele elicited only minor redox perturbations. Furthermore, the Cbs+/- genotype did not confer a significant disadvantage compared with the Cbs+/+ genotype in hepatocytes challenged by oxidative stress from exposure to tertiary butylhydroperoxide. These studies provide evidence that homozygous disruption of Cbs perturbs redox homeostasis and reduces cysteine levels, raising the possibility that these changes may be important in the etiology of the clinical manifestations of CBS deficiency.

• Authors: Victor Vitvitsky, Sanjana Dayal, Sally Stabler, You Zhou, Hong Wang, Steven R Lentz, Ruma Banerjee
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 287 Issue 1 Pg. R39-46 (Jul 2004) ISSN: 0363-6119 [Print] United States
• PMID: 15016621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Homocysteine
• Folic Acid
• tert-Butylhydroperoxide
• Methionine
• Glutathione
• Ascorbic Acid

Topics

• Animals
• Ascorbic Acid (metabolism)
• Blotting, Western
• Diet
• Folic Acid (metabolism)
• Glutathione (metabolism)
• Hepatocytes (metabolism)
• Homeostasis (physiology)
• Homocysteine (blood, metabolism)
• Methionine (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidation-Reduction
• Oxidative Stress (physiology)
• Tissue Distribution
• tert-Butylhydroperoxide (metabolism)