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PubMed2005

Absorption of interferon alpha from patches in rats.

Interferon alpha (IFN-alpha), patch preparations composed of three layers, water-insoluble backing layer, drug containing layer with absorption enhancer and surface layer containing pH-dependent polymer were prepared. As absorption enhancer, three surfactants, Gelucire44/14 (Lauroyl macrogol-32 glycerides), Labrasol (Caprylocaproyl macrogol-8 glycerides) and HCO-60 (polyoxyethylated hydrogenerated castor oil) were used in preparing IFN-alpha patch preparations. The intestinal absorption of IFN-alpha was studied after the administration of test patch preparations into the rat jejunum, 50,000 IU/kg. The serum IFN-alpha levels were measured by an ELISA method and both C(max) and AUC were determined as the index of absorption of IFN-alpha. Gelucire44/14 preparation including Pharmasol for the stable solidification showed the higher C(max), 7.66 +/- 0.82 IU/ml, and AUC, 12.85 +/- 1.49 IU h/ml, than Labrasol (6.51 +/- 0.89 and 8.30 +/- 1.34 IU h/ml) and HCO-60 (6.02 +/- 1.14, 7.53 +/- 1.84 IU h/ml) preparations, respectively. By comparing to the AUC obtained after s.c. injection of the same dose of IFN-alpha to rats, bioavailability (BA) was estimated to be 7.8% in Gelucire44/14 preparation. In vitro release study showed that the T50%s, the time when half of the formulated IFN-alpha is released from the patches, were 3.4 +/- 0.1 min for HCO-60, 7.8 +/- 0.1 min for Gelucire44/14 and 11.4 +/- 0.1 min for Labrasol preparations. To study the effect of absorption site, Gelucire44/14 preparation was administered into the rat duodenum and ileum. However, there were not significant differences on AUC among the three absorption sites. By reducing the IFN-alpha dose from 50,000 to 25,000 IU/kg, the serum IFN-alpha levels vs time profile showed a tendency of dose-dependency. When the histological examination of small intestinal mucosa was carried out in this study, the small intestinal mucosa after the Gelucire44/14 patches administered and before it was administered, could not recognize impaired. From these results, the usefulness of oral patch system for the oral delivery of IFN-alpha has been proved in rats.

Animals↗
PubMed2005

Final amended report on the safety assessment of Mink Oil.

Mink Oil, obtained from the fatty tissues of minks, is a mixture of the natural glycerides of 14 to 20 carbon chain fatty acids. There are 100 current reported uses as a hair-conditioning agent, an occlusive skin-conditioning agent, and as a surfactant; up to a maximum concentration of 3%. Mink Oil is manufactured by harvesting animal hides and scraping the fat layer from the hide. It is rendered and refined using high temperature processes (230 degrees F to 240 degrees F) and saponification to reduce free fatty acids. Analyses demonstrate that Mink Oil can be substantially free of impurities, including pesticides. Mink Oil does not absorb significant UVA or UVB radiation. In a clinical test of skin penetration, 1 h after application, Mink Oil was detected on the skin surface of all five panelists; it was detected within the stratum corneum in 2/5 panelists. Mink Oil has an oral LD50 of > 64.0 cc/kg in albino rats. No erythema or edema was noted after refined Mink Oil was applied for 24 h to intact and scarified area of albino rabbits. A 50% dilution of a Mink Oil cream did not sensitize guinea pigs in a maximization test. Mink Oil was not an ocular irritant to albino rabbits. Clinical studies using single occlusive patches found no irritation with up to 2.8% Mink Oil, although transient mild to no irritation was noted in two exaggerated-use studies. Mink Oil is used in aerosols and sprays. Although there are no inhalation toxicity data available on Mink Oil, the available data on particle sizes of cosmetic aerosols and sprays indicates diameters more than an order of magnitude larger than the diameter of respirable particles. Most of the glycerides in Mink Oil are triglycerides (glyceryl triesters), the safety of which has been substantiated in previous safety assessments; e.g., dermal absorption is nil to slight; there is little or no acute, subchronic, or chronic oral toxicity; dermal application was not associated with significant irritation or sensitization; ocular exposures were, at most, mildly irritating; most of the genotoxicity test systems are negative; use as vehicles in carcinogenicity testing of other chemicals has produced no adverse reaction; and clinical tests produce no irritation or sensitization reactions--but, they may enhance the of penetration of other chemicals. Formulators should be aware of the possible penetration-enhancing properties of Mink Oil. Although pesticide residues have been analyzed and found to be below levels of detection, the Panel is concerned that the available data suggesting the absence of pesticide residues in Mink Oil are limited. The Panel advised the industry that the total polychlorinated biphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue.

Adipose Tissue↗
PubMed1999

Effects of piperine on the lipid composition and enzymes of the pyruvate-malate cycle in the testis of the rat in vivo.

Effects of piperine at two oral doses (5 and 10 mg/kg body weight for 30 days) on the lipid composition and some lipogenic enzymes of the rat testis were studied. Piperine treatment depleted the total lipid content which was mainly due to the diminution of the total phospholipid concentration. All the classes of phospholipids were decreased markedly following high dose piperine treatment. In contrast, a marked increase in total cholesterol and cholesterol ester was evident with a concomitant fall in free cholesterol. A similar trend was found for the total glyceride glycerol and its fractions. Total glyceride glycerol and triacyl glycerol showed a significant increase at the expense of diacyl glycerol in rats treated with the high dose of piperine. Lipogenic enzymes, malate dehydrogenase (MDH), malic enzyme (ME) and isocitrate dehydrogenase (ICDH) were inhibited by the high dose and only MDH and ME activities were inhibited by the low dose treatment.

Administration, Oral↗
PubMed1986

The effects of galactolipid depletion on the structure of a photosynthetic membrane.

The galactolipids monogalactosyldiglyceride and digalactosyldiglyceride together comprise more than 77% of the photosynthetic membrane lipids of higher plant chloroplasts. We have isolated a lipase from the chloroplasts of runner beans (Phaseolus vulgaris) which is highly specific for these galactolipids. This galactolipase promotes the hydrolysis of monogalactosyldiglyceride and digalactosyldiglyceride, in the process liberating two free fatty acids into the membrane bilayer, leaving the residual galactosyl glyceride group to diffuse into the aqueous bulk phase. Isolated spinach photosynthetic membranes were treated with this enzyme preparation and changes in membrane composition were studied with thin layer chromatography (for lipids), gel electrophoresis (proteins), and freeze-etching (membrane structure). After 30 min of lipolysis, nearly 100% of the galactolipids had been converted into membrane-associated fatty acids and water-soluble galactosyl glycerides. SDS PAGE showed that two proteins, one of which is possibly associated with the reaction center of photosystem II, were removed by the treatment. Despite the minor nature of changes in membrane protein composition, freeze-fracture and freeze-etch studies showed that striking changes in membrane structure had taken place. The large freeze-fracture particle on the E fracture face had disappeared in stacked regions of the membrane system. In addition, a tetrameric particle visible at the inner surface of the membrane had apparently dissociated into individual monomeric particles. The fact that these two structures are so dramatically affected by the loss of galactolipids strongly suggests that these lipids play a crucial role in maintaining their structure. Both structures are believed to be different views of the same transmembrane unit: a membrane-spanning complex associated with photosystem II. Our results are consistent with two possible interpretations: the intramembrane particles may be lipidic in nature, and hence lipolysis causes their disappearance; or galactolipids are necessary for the organization of a complex photosystem II-associated structure which is composed of a number of different molecular species.

Carboxylic Ester Hydrolases↗
PubMed1967

Lipid synthesis, intracellular transport, and secretion. II. Electron microscopic radioautographic study of the mouse lactating mammary gland.

In the mammary glands of lactating albino mice injected intravenously with 9, 10-oleic acid-(3)H or 9, 10-palmitic acid-(3)H, it has been shown that the labeled fatty acids are incorporated into mammary gland glycerides. The labeled lipid in the mammary gland 1 min after injection was in esterified form (> 95%), and the radioautographic reaction was seen over the rough endoplasmic reticulum and over lipid droplets, both intracellular and intraluminal. At 10-60 min after injection, the silver grains were concentrated predominantly over lipid droplets. There was no concentration of radioactivity over the granules in the Golgi apparatus, at any time interval studied. These findings were interpreted to indicate that after esterification of the fatty acid into glycerides in the rough endoplasmic reticulum an in situ aggregation of lipid occurs, with acquisition of droplet form. The release of the lipid into the lumen proceeds directly and not through the Golgi apparatus, in contradistinction to the mode of secretion of casein in the mammary gland or of lipoprotein in the liver. The presence of strands of endoplasmic reticulum attached to intraluminal lipid droplets provides a structural counterpart to the milk microsomes described in ruminant milk.

Animals↗
PubMed1980

Metabolic responsiveness of different size adipocytes to fasting and refeeding in the pig.

The effects of fasting (F) and fasting-refeeding (FR) on [U-14C]glucose and [1-14C]palmitate metabolism were examined in pig middle subcutaneous (MSQ) adipocytes fractionated into 20--63, 63--102 and 102--153 microns diameter ranges. Fasting caused a similar decrease in de novo glyceride fatty acid (GFA) and glyceride-glycerol (GG) synthesis from glucose among adipocytes of different size. After refeeding for 2 days, glucose metabolism significantly increased in all fractions, however, the increase did not reach non-fasting levels. There was a disparate increase in glucose metabolism among adipocyte fractions after refeeding. Adipocytes 102--153 microns in diameter had a larger increase in glucose metabolism than smaller adipocytes. Fasting suppressed palmitate esterification rates in 20--63 and 63--102 microns fractions. Esterification by adipocyted 102--153 microns in diameter was not diminished after fasting. An "overshoot" in esterification by adipocytes 63--102 and 102--153 microns in diameter relative to control adipocytes was observed after refeeding; no "overshoot" occurred in 20--63 microns adipocytes. These results indicate that adipocytes of different size have markedly different capacities for substrate utilization after F or FR as well as different metabolic adaptations to F or FR.

Adipose Tissue↗
PubMed1975

Studies on plasma free-fatty-acid metabolism and triglyceride synthesis of brown adipose tissue in vivo during cold-induced thermogenesis of the newborn rabbit.

Parameters of plasma free fatty acid metabolism (pool size, half time, disappearance rate, turnover time and absolute turnover rate), the influx of plasma free fatty acids into the glycerides of brown adipose tissue and the pathway of triglyceride synthesis in brown adipose tissue (glycerol-1-phosphate versus monoglyceride pathway) were examined after intravenous injection of [1-14C]palmitate in newborn rabbits. In the thermoneutral environment of 35 degrees C the turnover rate of plasma free fatty acids was 10.20 mumol/min per 100 g body weight and its flux into the glycerides of brown adipose tissue 0.367 mumol/min per 100 g body weight. Cold exposure at an ambient temperature of 20 degrees C caused a decrease to 5.84 mumol/min and 0.207 mumol/min per 100 g body weight, respectively. Both under basal conditions at an ambient temperature of 35 degrees C and under cold-induced thermogenesis at an ambient temperature of 20 degrees C triglyceride synthesis in brown adipose tissue ran through the glycerol 1-phosphate pathway.

Adipose Tissue, Brown↗
PubMedDate not supplied

The lipid composition of human testis in patients with bilateral varicocele as cause of infertility.

The lipid composition of human testis in patients with bilateral varicocele as cause of infertility is presented. The total lipids formed 1.90 percent of the total wet weight of the tissue. Testicular cholesterol formed 26.50 percent, glycerides 28.50 percent and phospholipids 45 percent of the total lipids. The increase observed in total cholesterol, glycerides in the testis of patients with bilateral varicocele compared to the control group appears to suggest that non-utilization of cholesterol esters for androgen biosynthesis. Androgen deficiency would result in inhibition of spermatogenesis as shown by the histological examination of the bilateral testicular biopsy specimens. Testicular neutral lipids get altered whenever there is imparied steroidogenesis and spermatogenesis. Thus, testicular lipids may taken as one of the important indices of testicular function.

Adult↗
PubMed1983

Reversibility of propranolol-induced changes in the biosynthesis of monoacylglycerol, diacylglycerol, triacylglycerol, and phospholipids in the retina.

The biosynthesis and metabolism of phospholipids and neutral glycerides were studied in the bovine retina. Radioactive glycerol was used as a precursor. Phentolamine and d- and dl-propranolol were found to produce similar effects on lipid metabolism in the retina. Marked stimulation of phosphatidylinositol (PhI) synthesis and maximal inhibition of phosphatidylcholine (PhC), diacylglycerol (DG), and triacylglycerol (TG) formation were observed within 5 min after exposure to 0.5 mM dl-propranolol. Pulse-chase experiments showed a high turnover rate in DG and a reversibility of the propranolol-induced changes produced during the synthesis of PhC, TG, DG, monoacylglycerol (MG), and phosphatidylserine. All reversals of the drug-induced biosynthetic profiles approached control values 60 min after incubation in drug-free medium. However, complete reversal was not achieved in any of the cases under these conditions. Propranolol appeared to inhibit both the formation of DG from phosphatidic acid and the further metabolism of DG, probably to MG. Phosphatidylethanolamine biosynthesis showed some recovery from this inhibition. Synthesis of PhI was greatly stimulated by preincubation with propranolol and was further enhanced by reincubation in the presence of propranolol. However, this effect was not reversed by reincubation without the drug. The active de novo biosynthesis of retinal phospholipids and glycerides is a very dynamic pathway that may be redirected by amphiphilic drugs. In addition, the partial reversal of modifications induced in the flux of [2-3H]glycerol through the lipids can occur during short-term reincubations of retinas in drug-free medium.

Animals↗
PubMed1969

The effect of prolonged cold exposure on heat production in new-born rabbits.

1. The rates of oxygen consumption and the colonic temperatures were monitored from birth in rabbits delivered by Caesarean section at term. The rates of oxygen consumption at 25 and 36 degrees C rose over the first 12 hr of life.2. Thirty rabbits were kept unfed in an environment of 25 degrees C from birth. Extra oxygen consumption, in response to cold exposure, failed 24-34 hr later. Twenty-four of these rabbits were allowed to recover in an environment of 36 degrees C. The metabolic response to cold exposure did not return in those kept unfed or given glucose but those fed with rabbit's milk showed significant recovery when re-exposed to cold 4 or 18 hr later.3. The tissue glyceride content of brown and white adipose tissue and the liver were greatly reduced once the animals failed to respond to cold exposure and no significant rise was detected during the recovery period after a milk feed.4. Another twelve rabbits were kept unfed in an environment of 36 degrees C. These animals showed a poor metabolic response to cold exposure after 48 hr, although their brown adipose tissue was still replete with fat and the blood glucose rose to normal values during cold exposure.5. These results suggest that an increase in oxygen consumption in response to cold exposure can occur even though brown adipose tissue is largely depleted of glyceride provided that an alternative supply of fuel is available. Glucose alone is not an adequate source of energy.

Adipose Tissue↗
PubMed1993

Effects of cell density on in vitro glucose metabolism by isolated adipocytes.

We studied the effect of variable isolated fat cell concentrations (from 0.17 to 1.25 x 10(6) cells/ml) on rate and pattern of basal and insulin-stimulated glucose metabolism by rat epididymal fat cells. Cell concentration did not affect total glucose utilization, but high cell concentrations increased the absolute and relative conversion of glucose to CO2 and glyceride-fatty acids by two- to threefold and decreased the conversion to lactate, pyruvate, and glyceride-glycerol when compared with values observed at low cell concentration. When effects of adenosine deaminase (ADA) and N-6(2-phenylisopropyl)adenosine (PIA) were examined, addition of ADA to incubated cells produced no significant changes in the rate or pattern of adipocyte glucose metabolism; PIA had a slight and uniform effect on the conversion of glucose to its metabolic products and minimal effect on insulin-stimulated glucose metabolism. Medium free fatty acid concentration did not change during the incubation at various cell density, but intracellular free fatty acids were found to be inversely related to fat cell density in the medium. Thus a variable fat cell density influences the pattern of adipocyte glucose metabolism in vitro. This effect may be due to variable rates of lipolysis and resulting changes in intracellular fatty acid concentration rather than to adenosine per se. This work has practical implications in the need to define cell density when carrying out in vitro measurements of adipocyte glucose conversion to products.

Adenosine Deaminase↗
PubMed1975

Hormonal influence on testicular lipids.

The effects of progesterone and progesterone plus oestrogen (PPO) on testicular lipids of adult rats were studied. Treatment with progesterone over 7 days did not alter significantly the total lipids, cholesterol, glycerides and phospholipids. However, PPO administration brought about a significant elevation in total lipids, mainly contributed by the increase in triglycerides. The phospholipids and total cholesterol were not markedly affected by PPO treatment, but the individual classes of phospholipids showed marked alterations in their pattern of distribution. The esterified and free cholesterol fractions were found to be significantly altered by both the treatments. Progesterone appears to favour ester cholesterol accumulation by depleting the available free cholesterol. Oestrogen seems to increase the glycerides and change the concentration of phosphatidyl serine, phosphatidyl choline and phosphatidyl ethanolamine when administered with progesterone.

Animals↗
PubMed1978

The lipid composition of human testis in testicular feminization syndrome.

Testicular tissues obtained from 12 cases of testicular feminization syndrome were subjected to lipid analyses. The total lipids formed 2.75% of the total wet weight of the testicular tissue. Total cholesterol represented 30%, glycerides 33% and phospholipids 37% of the total lipids, respectively. Fractionation studies revealed that free cholesterol formed 66.7% and esterified cholesterol 33.3% of the total cholesterol. Triglycerides represented 89.89% and monoglycerides 10.11% of the total glycerides. Separation of phospholipids showed that phosphatidly choline (46.54%) and phosphatidly ethanolamine (24.89%) to be the major phosphoipid classes.

Adult↗
PubMed1979

Hormonal influence on uterine lipids.

The effects of oestrogen (OE), progesterone (P) and oestrogen plus progesterone (OEPP) on uterine lipids of adult ovariectomized rats were studied. Administration of gonodal hormones brought about considerable alterations in total lipids, mainly due to an increase in phospholipids and glycerides in the case of OE and P groups. Even though the total cholesterol remained unaltered, a marked alteration in its fractions was evident in all the groups. Oestrogen seems to decrease all the glyceride classes while progesterone induces accumulation ot triglycerides with concomitant decrease in mono- and diglycerides. Individual classes of phospholipids show marked alterations in their distribution in all the groups studied.

Animals↗
PubMed1980

Influence of hormones on testicular lipids of adult rats.

Testosterone, oestradiol-17 beta, progesterone and prolactin were administered for 1 and 7 days to adult rats to study the short- and long-term effects of these hormones on testicular lipids. Testosterone administration induced a marked increase in testicular phospholipids and a significant fall in glycerides. Oestrogen, on the other hand, provoked a significant increase in total lipids and glycerides with no marked changes in testicular phospholipids. Progesterone elicited significant changes in cholesterol fractions; a marked increase in esterified cholesterol with a concurrent fall in free cholesterol was observed. Prolactin treatment resulted in a significant fall in total lipids and phospholipids with no marked change in tissue weight. It also induced a marked fall in total and free cholesterol with a significant increase in esterified cholesterol.

Animals↗
PubMed1971

Inhibition of hepatic triglyceride formation by clofibrate.

The effect of clofibrate (CPIB) on hepatic glycerolipid formation has been studied in vivo and in vitro in the rat. Feeding 0.25% CPIB in laboratory chow significantly reduced serum triglyceride levels by 6 hr and concomitantly decreased the rate of glycerol-(14)C incorporation into hepatic and serum glycerides, in vivo. These changes persisted for at least 14 days. A similar decrease in serum triglyceride and glycerol incorporation into hepatic glycerides was observed in rats fed high glucose diets containing 0.25% CPIB. Serum glycerol was reduced by feeding CPIB for 14 days. The formation of diglyceride and triglyceride from (14)C-sn-glycerol-3-P by rat liver homogenates was inhibited by addition of 1-40 mM CPIB to the reaction mixture. These results suggest that CPIB reduces hepatic glycerolipid synthesis, possibly by inhibition of one or more reactions in the esterification of sn-glycerol-3-P. This change may account for the early fall in serum triglyceride. At later time periods, serum glycerol levels fall and in some experiments, hepatic triglyceride content increases. Therefore, it is likely that additional metabolic alterations may contribute to the sustained hypotriglyceridemic effects of CPIB.

Animals↗
PubMed1976

Cellular basis of insulin insensitivity in large rat adipocytes.

The marked stimulatory effect of insulin on the conversion of 20 mM D-[6-14C]glucose to CO2, glyceride-glycerol, and fatty acid observed in small rat adipocytes was greatly diminished in large cells from older rats. Similarly, total glucose utilization as estimated by summing the total metabolites accumulated intracellularly plus the release of labeled CO2 and lactate was substantially lower in large cells in the presence of insulin and 5 mM labeled glucose. However, under conditions of 0.2 mM medium glucose where transport of the hexose into adipocytes is relatively more rate-limiting for subsequent metabolism, large cells actually utilized slightly greater total amounts of glucose than small cells in the presence of insulin. Increments of total glucose utilization due to both submaximal and maximal doses of insulin were similar in large and small cells incubated with a low glucose concentration. Under these conditions, conversion of labeled glucose to CO2 and fatty acid in response to insulin was somewhat diminished in large cells, while conversion to glyceride-glycerol was enhanced. The activity of the D-glucose transport system in large and small cells was estimated by monitoring initial rates and small cells was estimated by monitoring initial rates of 3-O-[3H]methylglucose uptake by a rapid filtration method. Transport system activity on a per cell basis was actually severalfold higher in large adipocytes in the basal state as well as in the presence of submaximal and maximal concentrations of insulin compared to small cells. However, the percent stimulation by insulin was less in the large cells. Uptake of 2-deoxyglucose under basal conditions and in response to insulin was also higher in large cells compared to small cells. Analysis of the accumulated label in extracts from fat cells incubated with D-[14C]deoxyglucose revealed the presence of free deoxyglucose, deoxyglucose-6-phosphate, and 6-phosphodeoxygluconate. The levels of these metabolites were significantly higher in large cells compared to small cells indicating hexokinase activity appears not to account for the defective glucose utilization in large cells at high glucose concentrations. It is concluded that (a) possible defects in insulin receptor components, the D-glucose transport system, and the coupling mechanism which links these entities do not significantly contribute to the apparent insulin-insensitivity of large fat cells and (b) the principal cellular defect which confers this blunted insulin response to large rat adipocytes involves one or more intracellular enzymes involved in glucose metabolism.

Adipose Tissue↗
PubMedDate not supplied

New synthetic substrates for parenteral feeding.

The glycerol esters of short and medium chain fatty acids are predicted to become important in future nutritional therapy. These compounds provide a mixture of carbohydrate and "carnitine-independent" fat which, together, can serve more tissues than either substrate alone. Medium chain triglycerides are available for enteral feeding, and water-soluble monoglycerides are suggested for parenteral feeding. Two monoglycerides have been tested by continuous infusion into the rat and dog. Experimental evidence indicates rapid ester hydrolysis by endogenous mechanisms which release the basic components of the glycerides. Nutritional tests with these glycerides have produced results at least comparable to glucose as an energy source, and no toxicity has yet been noted. The data suggest that further investigations should be conducted on the benefits of these compounds.

Animals↗