Glutamine affects glutathione recycling enzymes in a DMBA-induced breast cancer model.
Malignancy depletes host glutathione (GSH) levels to increase treatment-related toxicity and increases itself to resist the treatments. Our previous studies have shown that dietary glutamine (GLN) prevented 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors through enhancing gut GSH release and reducing tumor GSH level. In addition, GSH synthesis, metabolism, and recycling are accomplished in gamma-glutamyl cycle. We hypothesized that the GLN prevention might be through a differential regulation of the gamma-glutamyl cycle enzymes. Female Sprague-Dawley rats were randomized into DMBA-tumor bearing, DMBA-treated, and control groups subdivided into GLN and water groups. GLN supplementation was given at 1 g/kg/day by gastric gavage. The activities and messenger RNA levels of gamma-glutamyl transpeptidase (GTP), gamma-glutamylcysteine synthetase (GCS), 5-oxo-L-prolinase (OPase), gamma-glutamyl transferase (GTF), and glutaminase (GLNase) were determined in gut mucosa and breast tumor using specific enzyme assays and semiquantitative reverse transcription polymerase chain reaction. GLN upregulated gut GTP, GCS, OPase, and GLNase in DMBA-tumor bearing, DMBA-treated, and/or control rats; however, it downregulated these enzymes in the tumor. The paradoxical effect of GLN on key GSH recycling enzymes in the gut versus tumor suggests that dietary supplemental GLN could be used in the clinical practice to increase the therapeutic index of cancer treatments by protecting normal tissues from, and sensitizing tumor cells to, chemotherapy and radiation-related injury.
Kaufmann
Yihong
Y
Medical Research Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA. kaufmannyihong@uams.edu
Todorova
Valentina K
VK
Luo
Shaoke
S
Klimberg
V Suzanne
VS
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D004032:Diet; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000737:chemistry / Q000201:enzymology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000201:enzymology*; D011752:Pyroglutamate Hydrolase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D012333:RNA, Messenger; D005973:Glutamine; D015127:9,10-Dimethyl-1,2-benzanthracene; D005723:gamma-Glutamyltransferase; D005972:Glutaminase; D011752:Pyroglutamate Hydrolase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione