homocysteine nrf2

1: Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G674-84. Epub 2005 Nov 23. Related Articles, Links
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Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells.

Wu D, Cederbaum AI.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.

S-adenosyl-L-methionine (SAMe) is protective against a variety of hepatotoxins, including ethanol. The ability of SAMe to protect against cytochrome P-450 2E1 (CYP2E1)-dependent toxicity was studied in hepatocytes from pyrazole-treated rats and HepG2 E47 cells, both of which actively express CYP2E1. Toxicity was initiated by the addition of arachidonic acid (AA) or by depletion of glutathione after treatment with L-buthionine sulfoximine (BSO). In pyrazole hepatocytes, SAMe (0.25-1 mM) protected against AA but not BSO toxicity. SAMe elevated GSH levels, thus preventing the decline in GSH caused by AA, and SAMe prevented AA-induced lipid peroxidation. SAMe analogs such as methionine or S-adenosyl homocysteine, which elevate GSH, also protected against AA toxicity. 5′-Methylthioadenosine (MTA), which cannot produce GSH, did not protect. The toxicity of BSO was not prevented by SAMe and the analogs because GSH cannot be synthesized. In contrast, in E47 cells, SAMe and MTA but not methionine or S-adenosyl homocysteine potentiated AA and BSO toxicity. Antioxidants such as trolox or N-acetyl cysteine prevented this synergistic toxicity of SAMe plus AA or SAMe plus BSO, respectively. In pyrazole hepatocytes, SAMe prevented the decline in mitochondrial membrane potential produced by AA, whereas in E47 cells, SAMe potentiated the decline in mitochondrial membrane potential. In E47 cells, but not pyrazole hepatocytes, the combination of SAMe plus BSO lowered levels of the antioxidant transcription factor Nrf2. Because SAMe can be metabolized enzymatically or spontaneously to MTA, MTA may play a role in the potentiation of AA and BSO toxicity by SAMe, but the exact mechanisms require further investigation. In conclusion, contrasting effects of SAMe on CYP2E1 toxicity were observed in pyrazole hepatocytes and E47 cells. In hepatocytes, SAMe protects against CYP2E1 toxicity by a mechanism involving maintaining or elevating GSH levels.

PMID: 16306132 [PubMed – indexed for MEDLINE]


2: J Biol Chem. 2005 Jan 14;280(2):872-7. Epub 2004 Nov 16. Related Articles, Links
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Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival.

Liu XM, Peyton KJ, Ensenat D, Wang H, Schafer AI, Alam J, Durante W.

Houston Veterans Affairs Medical Center and the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.

Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time- and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.

PMID: 15546873 [PubMed – indexed for MEDLINE]

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