Stereochemical aspects of the metabolism of 5-(4'-fluorophenyl)-5-phenylhydantoin in the rat.

Racemic 5-(4'-fluorophenyl)-5-phenylhydantoin was synthesized to examine its metabolism in rat. This compound differs from the antiepileptic agent 5,5-diphenylhydantoin in that the normal site of hydroxylation in 5,5-diphenylhydantoin is blocked on one of the phenyl groups by a fluorine atom. The 4'-fluoro analogue gives a major metabolite, which was isolated and identified as (R)-(-)-5-(4'-fluorophenyl)-5-(4'-hydroxyphenyl)hydantoin of 37% enantiomeric purity. The absolute configuration and enantiomeric purity of the metabolite was determined by chemical conversion to (S)-(-)-5-(4'-hydroxyphenyl)-5-phenylhydantoin. A second metabolite of the catechol type, possibly as a mixture of 5-(3',4'-dihydroxyphenyl)-5-(4'-fluorophenyl)hydantoin, and the corresponding O-3'-methyl derivative was detected by gas chromatography-mass spectrometry after methylation.

Hypothalamic and nutritional obesities in mice. A comparative study of growth and body composition.

Obesities induced in mice by a single injection of gold thioglucose or by a change to a fat-enriched diet(containing 8% fat) were studied in young and adult mice of Charles River strain. These two forms of obesity were compared and contrasted with normal animals maintained on 2.5% fat diet for life. The comparison was based on individual growth, age-realted fat, water and defatted dry weight of carcasses and their distribution of weights within larger populations. Young animals on diets containing 8% fat showed an elevated accumulation of fat but not of water. Individual variations lead to an abnormally distributed population where in some animals the excess in weight was characterized by an excessive fat and lean body mass and in others by an excess fat only. Some animals showed no excessive weight when compared to animals maintained on 2.5% fat. The rapid gain in weight which followed a successful injection with gold thioglucose showed a normal distrubution and was correlated with an accumulation of fat in young and adult animals. A significant retention of water was observed only in adults. The relative merits of these obesities as models for human regulatory obesities are briefly discussed.

Rate of incorporation of dietary fat in gold thioglucose obesity in mice.

Gold Thioglucose injections in mice are followed by a rapid accumulation of fat in the carcasses. The incorporation of an oral dose of [3H] glyceroyl tripalmitate in body fat stores showed after GTG-treatment a transient but significant increase and a return to normal values within 6 weeks. The rate of incorporation of dietary fat into the body was estimated from these values as well as from food intake and fat content of the diet (2.5 per cent). The resulting curve showed great similarity with the first differential of the curve of total body fat accumulated during that period. The rate of incorporation of dietary fat into body stores is apparently modified in GTG obesity in mice.

Food and water intake in gold thioglucose-induced obese Charles River mice.

Food and water intake have been measured during the dynamic phase of gold thioglucose-induced obesity in Charles River mice. Regressions of gain in weight with food and water consumption were calculated in young growing animals and in adults fed ad libitum. The influence of fat content in the diet (2.5 and 8% fat) and environmental temperature (68degrees or 79degrees F) was estimated on the regressions. Excessive gain in weight without hyperphagia was observed in growing animals, in adults fed on a fat-enriched diet or maintained within a thermoneutral environment (79degrees F). But a significant hyperphagia was observed in adults fed with a conventional diet and maintained at 68degrees F or in growing animals as a sequela of food deprivation.

Membrane digestion and nutrient assimilation in early development.

Advances in the study of membrane digestion are described which relate to techniques for the separation of the apical glycocalyx and the study of the distribution of enzymes between the latter and the cell membrane. The regulatory properties of brush border enzymes have been demonstrated. Membrane digestion by pancreatic enzymes adsorbed on the mucosal surface and by enteric enzymes predominates in early development, whereas intraluminal digestion develops during the transition to definitive (adult) nutrition. Substrate and other, non-substrate factors are involved in the regulation of intraluminal and membrane digestion in ontogeny. The importance of lipid components of the diet for the maintenance of proximal-distal gradients of enzyme activity in the small intestine during the transition from milk to adult nutrition is discussed. At this period of development hydrocortisone affects both the synthesis of enzymes and their incorporation into the enterocyte membrane. The inducibility of different enzymes is not identical. The hypothesis has been proposed that stress is one of the factors inducing or repressing the synthesis of brush border enzymes. These effects are mediated through the hypothalamus, adrenals, hypophysis and thyroid. The experimental findings demonstrate that various stressors are responsible for the induction of sucrase, maltases, gamma-amylase, peptidases and alkaline phosphatase, and for the repression of lactase in suckling rats.

Substrate interactions on the intestinal mucosa: a concept for the regulation of intestinal digestion.

1. The hydrolysis of glycyl-L-leucine, glycyl-L-tyrosine, tributyrin, sucrose, maltose, soluble starch and alpha- and beta-glycerophosphates by everted segments of rat intestine was estimated separately or in combination. 2. A comparative study showed significant interaction between different substrates which affected their digestion. 3. Two types of interaction were identified: products of hydrolysis (1) affected the hydrolysis of homologous substances, e.g. methionine and alanine inhibited glycyl-L-leucine hydrolysis, maltose reduced glucoamylase (alpha-1,4-glucan glucohydrolase; EC 3-2-1-3) activity (intracatenary interactions); (2) interfered with the hydrolysis of a different group of substances, e.g. tributyrin inhibited dipeptidase (glycyl-L-leucine hydrolase; EC 3-4-3-2) and alkaline phosphatase (EC 3-1-3-1), glycyl-L-leucine interfered with the activity of the latter enzyme (intercatenary interactions). 4. Mechanisms of interactions were suggested by the results of a comparison of the extent of inhibition or activation of two enzymes (glycyl-L-leucine hydrolase and alkaline phosphatase) in situ in everted intestinal segments or after solubilization with papain or Triton X-100, and different treatments known to affect allosteric sites of these enzymes. 5. Tributyrin and dipeptides were found to act on alkaline phosphatase as allosteric regulators. A discontinuity of the Arrhenius plot suggested the existence of different enzyme conformations which were re-arranged by tributyrin. 6. Substrate interactions in digestion were found in adult rat, cat, rabbit and hen. Substantial differences were found between classes (Aves and Mammalia), orders (rodents, lagomorphs and carnivores) and between age-groups within an animal strain (in this instance, for the rat). 7. These interactions are thought to be involved in the co-ordination of digestion with intestinal absorption and to regulate the time and site of subsequent hydrolysis.