Oral glutamine prevents DMBA-induced mammary carcinogenesis via upregulation of glutathione production.
OBJECTIVE
Glutamine is suggested to participate in glutathione synthesis. Furthermore, there is a positive relation between glutathione level and natural killer (NK) cell activity. Previously we demonstrated that supplemental glutamine inhibited tumor growth in an implantable tumor model and 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral squamous cell carcinoma model; these reductions were associated with enhancing NK cell cytotoxicity, blood glutathione levels, and/or gut glutathione release. Therefore, we hypothesized that oral glutamine might suppress DMBA-induced mammary carcinogenesis by upregulation of glutathione production and/or augmentation of NK cell activity.


METHODS
Rats were randomized to six groups: DMBA + glutamine, DMBA + Freamine, DMBA + water, oil + glutamine, oil + Freamine, or oil + water. At age 50 d, rats were gavaged with DMBA or sesame oil. Rats also received glutamine, Freamine, or water by gavage from 1 wk before DMBA administration until sacrifice at 1, 2, 4, or 11 wk after DMBA. Tumor appearance, blood, gut mucosa and breast glutamine and/or glutathione concentrations, and NK cell cytotoxicity were measured. The gut extractions, defined as the difference of concentrations across the gut, were calculated.


RESULTS
Oral glutamine reduced the tumorigenesis of DMBA by 50% in this model. DMBA altered the difference of glutathione concentrations across the gut; however, oral glutamine maintained the normal gut glutathione release. NK cell activities were lower in DMBA groups at early (week 1) and late (week 11) time points, but oral glutamine recovered the NK cell activity only at week 11. In addition, blood, gut, and breast glutathione concentrations were enhanced by glutamine supplementation.


CONCLUSIONS
These results indicate that one of the mechanisms of dietary glutamine anticancer action is through upregulating gut glutathione metabolism.
Kaufmann
Yihong
Y
Medical Research Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. kaufmannyihong@uams.edu
Spring
Paul
P
Klimberg
V Suzanne
VS
D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005973:Glutamine / Q000008:administration & dosage*; D005978:Glutathione / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D005973:Glutamine; D015127:9,10-Dimethyl-1,2-benzanthracene; D005978:Glutathione