Oral glutamine protects against cyclophosphamide-induced cardiotoxicity in experimental rats through increase of cardiac glutathione.
OBJECTIVE
This study evaluated the effects of supplemental oral glutamine (GLN) on acute cardiotoxicity of cyclophosphamide (CPA) in experimental rats. The dose-related cardiotoxicity of CPA is associated with a rapid decrease in cardiac glutathione (GSH) and oxidative cardiac injury. GLN is a rate-limiting precursor for GSH synthesis during periods of oxidative and other types of stress when it becomes a conditionally essential amino acid.


METHODS
Forty-four male Fischer 344 rats were randomized into two groups to receive 1 g.kg(-1).d(-1) of GLN or glycine by gavage. After 2 d of prefeeding, each of these groups was further randomized into three subgroups to receive intraperitoneally a lethal dose of CPA (450 mg/kg), a sublethal dose of CPA (200 mg/kg), or saline (controls). Twenty-four hours later all six groups of rats were sacrificed and blood GLN was measured. Cardiac tissue was examined for histopathologic alterations: GSH and oxidized GSH concentrations.


RESULTS
The results showed that dietary GLN decreased cardiac necrosis and maintained normal cardiac GSH levels. Elevated cardiac GSH levels in the GLN group correlated with increased arterial GLN levels. GLN protected against the acute cardiotoxic effects of CPA and significantly improved the short-term survival after lethal and sublethal doses of CPA.


CONCLUSIONS
These data suggest that GLN may protect against CPA-related cardiac injury through maintenance of cardiac GSH metabolism.
Todorova
Valentina
V
Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, USA. todorovavalentinak@uams.edu
Vanderpool
Doug
D
Blossom
Sarah
S
Nwokedi
Emmanuel
E
Hennings
Leah
L
Mrak
Robert
R
Klimberg
V Suzanne
VS
D000284:Administration, Oral; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity*; D004195:Disease Models, Animal; D005973:Glutamine / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism*; D005998:Glycine / Q000494:pharmacology / Q000627:therapeutic use; D006331:Heart Diseases / Q000517:prevention & control*; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000517:prevention & control; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
D018906:Antineoplastic Agents, Alkylating; D005973:Glutamine; D003520:Cyclophosphamide; D005978:Glutathione; D005998:Glycine