EFFECTS OF ENDOTOXIN CHALLENGE ON HEPATIC AMINO-ACID-TRANSPORT DURINGCANCER

Background. The hepatic uptake of amino acids is increased in both sep sis and cancer, and this response appears to be both global and essent ial in the catabolic host. Because immunocompromised cancer patients a re susceptible to episodes of gram-negative sepsis, we examined the ca pacity of hepatocytes from normal and tumor-influenced livers to respo nd 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. Materials and methods. Fischer 344 rats were implanted with methylcholanthrene-induced fibrosarcomas. Control rats were sham-operated and pair-fed. Animal pairs (tumor burden = 8-3 2% carcass weight) were injected intraperitoneally with either Escheri chia 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 ra tes were measured using radiolabeled glutamine for System N and alpha- methylaminoisobutyric acid (MeAIB), a nonmetabolizable substrate speci fic for System A. Results. Cancer - independent of tumor size - and en dotoxin each elicited similar 1.5- to 2-fold inductions of System N ac tivity. When combined, their effects mere additive rather than synergi stic. In contrast, endotoxin induced an insignificant increase in Syst em A activity, whereas cancer stimulated this carrier 2-fold in either the-absence or the presence of endotoxin. Conclusions. The primary gl utamine and alanine carriers in hepatocytes are differentially influen ced during catabolic states, and the tumor-influenced liver is compete nt to further increase glutamine uptake in response to additional cata bolic insults. (C) 1998 Academic Press.