The amino acid, glycine (Gly), is known to protect the isolated liver and kidney from hypoxia/reperfusion injury, hepatocytes from H202-induce injury, and endothelial cells and lung from oxidant- induced injury. In more recent in vivo studies, a Gly-supplemented diet fed to rats has been shown to (a) increase plasma Gly levels, (b) protect the liver from chronic ethanol-induced injury, (c) attenuate organ injury and prevent mortality in LPS-induced sepsis, and (d) block cyclosporine- induced kidney injury. While th cytoprotective properties of Gly are impressive and have been described in som detail, its mechanism of protection is unknown. None of the proposed mechanism in the literature adequately account for the protective effects of Gly against oxidative stress-induced cell and tissue injury. Nitric oxide (NO) is considered to have cytoprotective as well as cytotoxic properties, and the now well described Gly protection in several cell types an organs led us to consider the possibility that NO derived from Gly may mediate the protective effects of this amino acid. Our hypothesis implies the existenc of a non-NO synthase (NOS) pathway for the production of NO from Gly, which is distinct from the C-NOS and I-NOS catalyzed oxidations of arginine to NO. Accordingly, we are proposing a series of studies designed to (a) show that Gly is oxidized to NO through a non-NOS pathway using 15N-Gly as tracer (b) describe this non-NOS pathway for the conversion of Gly to NO, and (c) demonstrate that the Gly protection against H202-induced injury in isolated hepatocytes is mediated, at least in part, by NO derived from the amino group of Gly. We suggest that this mechanism of protection is a normal physiological process even in the absence of dietary Gly supplementation, and speculate that enhance dietary Gly and serine, the latter a biochemical precursor of Gly, may influence the onset and course of selective oxidative stress- induced cellular injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21GM058174-02
Application #
6019495
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1998-08-01
Project End
2000-10-31
Budget Start
1999-08-01
Budget End
2000-10-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455