Analysis of liver tissue for olestra following long-term feeding to rats and monkeys.

The potential for olestra to be absorbed and to accumulate in tissues was investigated by analysing liver tissue from rats and monkeys in long-term feeding studies using sensitive chromatographic methods. Studies with intravenously administered olestra indicated that absorbed olestra is predominantly taken up by the liver. In monkeys, 74% of the injected dose was detected in the liver, as intact olestra, 48 hr after dosing. In rats, 58-96% of the injected dose was found in the liver, as intact olestra, within 24 hr. No olestra was detected (limit, 34 micrograms/g) in the livers of 14 monkeys fed olestra at 8% of the diet for 29 months. Also, no olestra was found in samples of liver, heart, kidney, spleen, lymph nodes and adipose tissues from 26 monkeys fed olestra at 0, 2, 4 or 6% of the diet, in random order, for consecutive 2-month periods. No olestra was detected in the livers of 47 out of 50 rats fed olestra at levels of up to 9% of the diet for up to 2 years. The amounts (2-4 micrograms/g) detected in the other three rats were near the detection limit of the chromatographic method (1.6 micrograms/g). The results show that accumulation of olestra in the liver, the primary target organ for absorbed olestra, was less than 3 x 10(-6)% of the total amount eaten by rats over 24 months and less than 4 x 10(-5)% of the amount eaten by monkeys over 29 months. These results are consistent with previous studies which showed that olestra is essentially not absorbed from the gastro-intestinal tract.

Effect of charge on hepatic specific nature of vesicle encapsulated insulin in conscious dogs.

Positively [(+)-VEI] and negatively [(-)-VEI] charged formulations of vesicle encapsulated insulin (VEI) were compared with insulin on the basis of their ability to suppress hepatic glucose production (hepatic Ra) and stimulate glucose utilization (Rd) in conscious dogs. Our results indicate that (-)-VEI and insulin have an equivalent capacity to suppress hepatic glucose production at dose levels of 0.2, 1.2, and 2.4 mU X kg-1 X min-1. (+)-VEI is less effective at suppressing hepatic Ra than both insulin and (-)-VEI at dose levels of 1.2 and 2.4 mU X kg-1 X min-1. Both (+)-VEI and (-)-VEI induced significantly less glucose utilization than a comparable amount of insulin at dose levels of 1.2 and 2.4 mU X kg-1 X min-1. The amount of glucose utilization stimulated by (+)-VEI was significantly less than that induced by insulin at 0.6 mU X kg-1 X min-1. This difference was not evident with (-)-VEI. These results suggest that the insulin contained in (+)-VEI is less bioavailable than that contained in (-)-VEI. This difference in bioavailability is believed to be the result of greater serum stability of (+)-VEI vesicles when compared with that of (-)-VEI. In conclusion, both (+)-VEI and (-)-VEI have the capacity to shield encapsulated insulin from interacting with peripheral tissues and deliver insulin selectively to the liver. Both formulations afford one an opportunity to expand the therapeutic window for hepatically active compounds where their utility is limited by systemic toxicity.

Assessment of the nutritional effects of olestra, a nonabsorbed fat replacement: introduction and overview.

Olestra is a mixture of polyesters formed from sucrose and fatty acids derived from edible fats and oils. It is not absorbed or digested and can serve as a zero-calorie replacement for dietary fat. Because olestra is lipophilic and not absorbed, it has the potential to interfere with the absorption of other dietary components, especially lipophilic ones, when it is in the digestive tract with those components. A series of studies were conducted in the domestic pig and in healthy adult humans to define the nature and extent of olestra's effect on fat-soluble vitamins, selected water-soluble micronutrients, and macronutrients, and to demonstrate that the effects of olestra on the absorption of fat-soluble vitamins can be offset by adding extra amounts of the affected vitamins to olestra foods. Before conducting the human and pig studies, the intake of olestra from the consumption of snack foods made with olestra was estimated for various subgroups. The potential for olestra to affect the absorption of nonessential but potentially beneficial dietary phytochemicals was also assessed. In addition, an assessment of how consumption patterns influence the effect of olestra on the absorption of the highly lipophilic carotenoids was made. Finally, the results from the pig and human studies were used to assess the potential for olestra to affect the nutritional status of subgroups of the population who have particularly high nutrient needs or unique dietary patterns that may lead to large olestra-to-nutrient intake ratios.

Assessment of the nutritional effects of olestra, a nonabsorbed fat replacement: summary.

Olestra is a zero-calorie fat replacement intended to replace 100% of the fat used in the preparation of savory snacks. Olestra can affect the absorption of other dietary components, especially highly lipophilic ones, when ingested at the same time. The potential effects of olestra on the absorption of essential fat-soluble and water-soluble dietary components have been investigated in pigs and in humans. In these studies, subjects were fed daily amounts of olestra up to 10 times the estimated mean intake from savory snacks and the olestra was eaten each day of the studies. In real life, snacks are eaten on average five times in a 14-d period. Olestra did not affect the availability of water-soluble micronutrients or the absorption and utilization of macronutrients. Olestra reduced the absorption of fat-soluble vitamins A, D, E and K; however, the effects can be offset by adding specified amounts of the vitamins to olestra foods. Olestra also reduced the absorption of carotenoids; analysis of dietary patterns showed that in real life the reduction will likely be <10%. Any effect on vitamin A stores caused by a reduction in carotenoid uptake is offset by the addition of vitamin A to olestra foods. Because of the olestra-to-nutrient ratios fed and the nutritional requirements of the test subjects, the effects of olestra on nutritional status of subgroups of the population are unlikely to be different than those measured in the studies. An analysis of lipophilicity showed that olestra is unlikely to significantly affect the uptake of potentially beneficial phytochemicals from fruits and vegetables. Some people eating large amounts of olestra snacks may experience common GI symptoms such as stomach discomfort or changes in stool consistency, similar to symptoms accompanying other dietary changes. These symptoms present no health risks.

Re-evaluation of amino-oxyacetate as an inhibitor.

Data are provided which indicate that pyruvate and/or acetaldehyde can reverse the inhibition of alanine aminotransferase and aspartate aminotransferase by amino-oxyacetate. It was shown that acetaldehyde could reverse the inhibition of gluconeogenesis from alanine and that pyruvate could reverse the inhibition of urea synthesis by amino-oxyacetate.

Metabolism of D- and L-tryptophan in dogs.

The metabolism of D- and L-[benzene ring-U-14C]tryptophan by dogs was studied. The distribution of label from each isomer in urine, feces, CO2 and various tissues was determined. Thirteen different urinary tryptophan metabolites were isolated by ion exchange cellulose chromatography. D-[14C]Tryptophan was poorly converted to 14CO2 relative to the L-isomer, while giving rise to nearly three times as much urinary 14C as did the L-isomer. The major urinary metabolites of D-tryptophan were unchanged D-tryptophan via indolepyruvic acid appeared to be the major fate of ingested D-tryptophan, with renal excretion of the unchanged D-isomer the next most important fate. The dog apparently utilizes D-tryptophan more efficiently than does the human but much less efficiently than does the rat. The dog appears to be a reasonable animal model for the human in studies of D-tryptophan metabolism.

Transport of lysine and hydroxylysine in Streptococcus faecalis.

Data are presented which support the view that l-lysine is transported by two systems in Streptococcus faecalis. The system with the higher affinity for l-lysine appears to be specific for l-lysine among the common amino acids and to require an energy source. The second system transports both l-lysine and l-arginine and does not appear to require an energy source. Both of these systems will accept hydroxy-l-lysine as a substrate as shown by the energy requirement for hydroxy-l-lysine transport and by the inhibition of uptake by l-arginine as well as by l-lysine. The affinity of both systems appears to be considerably lower for hydroxy-l-lysine than for l-lysine. A mutant of S. faecalis which is resistant to the growth inhibitory action of hydroxy-l-lysine appears to differ from the parent strain by having a defective l-lysine-specific transport system. In this mutant, hydroxy-l-lysine is not readily transported via the l-lysine-specific system because of the mutation or via the second system because of the high concentration of l-arginine present in the growth medium. This overall lack of transport prevents hydroxy-l-lysine from reaching inhibitory levels within the cell.