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We determined the contribution from host hepatic and extrahepatic tissues to newly synthesized fatty acids (FA) in the Ehrlich ascites tumor (EAT). We administered 3H2O (subcutaneously) and [14C]glucose (in a test meal) and measured the appearance of radioactivity in plasma triglyceride fatty acids (TGFA) and free fatty acids (FFA) and in tumor total lipid fatty acids (TLFA). Using [14 C]FFA, we selectively labeled epididymal fat TGFA to estimate the FA transport rate from intraperitoneal adipose tissue directly to the tumor. Contributions of four major pathways to newly synthesized FA in EAT were determined by multicompartmental analysis. De novo FA synthesis by EAT accounted for more than 93% of the TLFA radioactivity found in the tumor. Contributions from liver TGFA via plasma TGFA (less than 0.5%), adipose tissue TGFA via plasma FFA (less than 6%), and adipose tissue TGFA via direct intraperitoneal transport of FFA (less than 1%) accounted for less than 7% of all TLFA radioactivity measured in the EAT. Thus the present study establishes that practically all labeled esterified FA in the EAT is derived from de novo synthesis by tumor cells.

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Children who had presented with transient neonatal tyrosinaemia (TNT) were compared with a group of unaffected controls at 7-9 years of age. A comprehensive psychometric assessment revealed significant differences between the groups in adaptive behaviour, psycholinguistic abilities, and speed of learning. In nearly all components of the tests used, higher levels of TNT were associated with lower levels of performance. This study demonstrates that TNT, a condition commonly regarded as benign in the short term, has long-term effects which may be detrimental to the child in school.

Using isolated, in situ, single-pass perfused rat livers, incubations of freshly isolated hepatocytes, and sinusoidal membrane-enriched vesicles, we and others have shown the saturability of transport (efflux) of hepatic glutathione (GSH). These observations have implicated a carrier mechanism. Our present studies were designed to provide further evidence in support of a carrier mechanism for hepatic GSH efflux by demonstrating competition by liver-specific ligands which are taken up by hepatocytes. Perfusing livers with different substances, we found that: (a) sulfobromophthalein-GSH (BSP-GSH) had a dose-dependent and fully reversible inhibitory effect on GSH efflux, while GSH alone did not have any effect; (b) taurocholate had no inhibitory effect; (c) all of the organic anions studied, i.e., BSP, rose bengal, indocyanine green, and unconjugated bilirubin (UCB), manifested potent, dose-dependent inhibitory effects, with absence of toxic effects and complete reversibility of inhibition in the case of UCB. The inhibitory effects of UCB could be overcome partially by raising (CoC12-induced) hepatic GSH concentration.Because of the physiological importance of UCB, we conducted a detailed study of its inhibitory kinetics in the isolated hepatocyte model in the range of circulating concentrations of UCB. Studies with Cl1-free media, to inhibit the uptake of UCB by hepatocytes, showed that the inhibition of GSH efflux by UCB is apparently from inside the cell. This point was confirmed by showing that the inhibition is overcome only when bilirubin-loaded cells are cleared of bilirubin (incubation with 5% bovine serum albumin). Using Gunn rat hepatocytes and purified bilirubin mono-and diglucuronides, we found that both UCB and glucuronide forms of bilirubin inhibit GSH efflux in a dose-dependent manner. We conclude that the organic anions, although taken up by a mechanism independent of GSH, may competitively inhibit the carrier for GSH efflux from inside the hepatocyte.

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