Effects of endotoxin challenge on hepatic amino acid transport during cancer.
BACKGROUND
The hepatic uptake of amino acids is increased in both sepsis and cancer, and this response appears to be both global and essential in the catabolic host. Because immunocompromised cancer patients are susceptible to episodes of gram-negative sepsis, we examined the capacity of hepatocytes from normal and tumor-influenced livers to respond to the additional challenge of endotoxemia via increases in the Na+-dependent uptake of glutamine and zwitterionic amino acids by System N and System A, respectively.


METHODS
Fischer 344 rats were implanted with methylcholanthrene-induced fibrosarcomas. Control rats were sham-operated and pair-fed. Animal pairs (tumor burden = 8-32% carcass weight) were injected intraperitoneally with either Escherichia coli endotoxin (10 mg/kg) or PBS, and after 4 h, hepatocytes were isolated from the livers of the animals via collagenase perfusion and placed in primary culture. Three hours later, amino acid transport rates were measured using radiolabeled glutamine for System N and alpha-methylaminoisobutyric acid (MeAIB), a nonmetabolizable substrate specific for System A.


RESULTS
Cancer-independent of tumor size-and endotoxin each elicited similar 1.5- to 2-fold inductions of System N activity. When combined, their effects were additive rather than synergistic. In contrast, endotoxin induced an insignificant increase in System A activity, whereas cancer stimulated this carrier 2-fold in either the absence or the presence of endotoxin.


CONCLUSIONS
The primary glutamine and alanine carriers in hepatocytes are differentially influenced during catabolic states, and the tumor-influenced liver is competent to further increase glutamine uptake in response to additional catabolic insults.
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA.
A M
AM
Easson
B P
BP
Bode
C P
CP
Fischer
W W
WW
Souba
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D005354:Fibrosarcoma / Q000139:chemically induced / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000378:metabolism
D000596:Amino Acids; D004731:Endotoxins; D008070:Lipopolysaccharides; D005973:Glutamine; D015091:beta-Alanine; C012924:2,2-dimethyl-beta-alanine; D008748:Methylcholanthrene