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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 91 records · Page 5Linked to original sources
PubMed1995

Distribution of plasma phosphatidylcholine molecular species in rabbits fed fish oil is modulated by dietary n-6 fatty acids.

The present study examined the distribution of plasma phosphatidylcholine (PC) molecular species in rabbits fed a chow diet supplemented with fish oil (FO) in combination with either hydrogenated coconut oil or the n-6 fatty acid-rich evening primrose oil (EPO) for 4 weeks. Significant proportions of plasma PC molecular species contained long-chain n-3 fatty acids. Addition of EPO to the FO supplemented diet increased the incorporation of n-6 fatty acids into plasma PC molecules; it also raised the proportions of 16:0-18:2, n-6, 18:1-18:2, n-6, 18:2, n-6-18:2, n-6, and 16:0-20:4, n-6. The increase of n-6 fatty acid-containing PC was at the expense of n-3 fatty acid containing PC species. However, feeding n-6 fatty acids did not affect the distribution of PC molecular species based on total carbon chain length. The most interesting observation was that dietary suplementation with EPO, raised the ratio of 22:6, n-3-containing to 20:5, n-3-containing molecular species, suggesting an enhanced conversion of 20:5, n-3 to 22:6, n-3.

Animals↗
PubMed1995

Inhibition of hepatocyte growth factor-induced motility and in vitro invasion of human colon cancer cells by gamma-linolenic acid.

In this study we have determined the effects of the n-6 essential fatty acid gamma-linolenic acid (GLA) on the motility and invasive/metastatic nature of the human colon cancer cell lines HT115, HT29 and HRT18. Cell motility was induced by hepatocyte growth factor/scatter factor (HGF/SF) and measured by both colony scattering and dissociation from carrier beads. Invasiveness was measured in vitro by cellular invasion into extracellular matrix. At concentrations up to 100 microM (which had no effect on cell growth over the duration of the experiments) both cell motility and invasion induced by HGF/SF were markedly reduced by GLA and its lithium salt. The attachment of these cells to the extracellular matrix components (Matrigel and fibronectin) was also inhibited. There were also changes in the cell-surface E-cadherin, but not fibronectin receptor at similar concentrations. It is concluded that n-6 essential fatty acids have the ability to inhibit both motility and invasiveness of human colon cancer cells, perhaps by modifying cell-surface adhesion molecules.

Arachidonic Acid↗
PubMed1994

Amelioration of both early and late radiation-induced damage to pig skin by essential fatty acids.

PURPOSE: To evaluate the possible role of essential fatty acids, specifically gamma-linolenic and eicosapentaenoic acid, in the amelioration of early and late radiation damage to the skin. METHODS AND MATERIALS: Skin sites on the flank of 22-25 kg female large white pigs were irradiated with either single or fractionated doses (20 F/28 days) of beta-rays from 22.5 mm diameter 90Sr/90Y plaques at a dose rate of approximately 3 Gy/min. Essential fatty acids were administered orally in the form of two 'active' oils, So-1100 and So-5407, which contained gamma-linolenic acid and a mixture of that oil with eicosapentaenoic acid, respectively. Oils (1.5-6.0 ml) were given daily for 4 weeks prior, both 4 weeks prior and 10-16 weeks after, or in the case of one single dose study, just for 10 weeks after irradiation. Control animals received a 'placebo' oil, So-1129, containing no gamma linolenic acid or eicosapentaenoic acid over similar time scales before and after irradiation. Acute and late skin reactions were assessed visually and the dose-related incidence of a specific reaction used to compare the effects of different treatment schedules. RESULTS: A reduction in the severity of both the early and late radiation reactions in the skin was only observed when 'active' oils were given over the time course of the expression of radiation damage. Prior treatment with oils did not modify the radiation reaction. A 3.0 ml daily dose of either So-1100 or So-5407 given prior to, but also after irradiation with single and fractionated doses of beta-rays produced the most significant modification to the radiation reactions, effects consistent with dose modification factors between 1.06-1.24 for the acute reactions of bright red erythema and/or moist desquamation, and of 1.14-1.35 for the late reactions of dusky/mauve erythema and dermal necrosis. There was the strong suggestion of an effect produced by the 'placebo' oil, So-1129, after higher daily doses of oil. CONCLUSIONS: Essential fatty acids can modulate normal tissue reactions when given over the time when radiation damage is normally expressed. Dose modification factors suggest that a > or = 10% higher dose is required to produce the same level of normal tissue injury. Clinical application of selected essential fatty acids at appropriate doses may lead to a significant increase in the therapeutic gain in patients treated for cancer by radiotherapy.

Animals↗
PubMed1994

Metabolism of n-6 fatty acids by NIH-3T3 cells transfected with the ras oncogene.

N-6 fatty acid metabolism was compared in NIH-3T3 cells and DT cells, which differ only in the presence of the v-Ki-ras oncogene. Non-dividing cells were incubated with [1-14C]-labelled fatty acids (18:2n-6, 18:3n-6, 20:3n-6 and 20:4n-6) at different time intervals (2-24 h) and concentration (0-120 microM). In both cells lines, the uptake of different fatty acids from the medium was similar and reached a maximum at 6-8 h. All fatty acids reached the same maximum level in DT cells, whereas, the relative uptake of added fatty acids by NIH-3T3 cells was different: 20:4n-6 > 20:3n-6 > 18:2n-6 = 18:3n-6. Throughout the incubation (2-24 h), desaturation and elongation of n-6 fatty acids was more active in DT cells than in NIH-3T3 cells. However, in both cell lines, incubated with different n-6 fatty acid precursors, the levels of radiolabelled 20:4n-6 were relatively constant. In DT cells, phosphatidylcholine was found to be the major fraction labelled with n-6 fatty acids precursors and those of endogenous synthesis, whereas, in NIH-3T3 cells the neutral lipid fraction, particularly triglycerides, was also strongly labelled. In concentration dependent studies, phospholipid labelling by fatty acids was saturable. At lower concentrations, especially in DT cells, phospholipids were labelled predominantly. As the concentration increased there was an overflow into the triglyceride fraction. Since the differences in fatty acid metabolism between the two cell lines cannot be related to the growth rate, it is suggested that they were a consequence of the expression of the v-Ki-ras oncogene.

3T3 Cells↗
PubMed1994

Differences in the metabolism of 18:2n-6 and 18:3n-6 by the liver and kidney may explain the anti-hypertensive effect of 18:3n-6.

The present study examined the in vitro and in vivo metabolism of 18:2n-6 and 18:3n-6 by kidney and liver in the male adult spontaneously hypertensive (SHR) and normotensive (WKY) rats. In liver and kidney slices incubated for 1 h with either [1-14C]18:2n-6 or [1-14C]18:3n-6 (60 microM), substantial amounts of radioactivity were incorporated into triacylglycerol and phospholipid fractions. Approximately 15% of the radiolabeled 18:2n-6 was converted into 18:3n-6 in liver slices but no conversion was found in kidney slices. When incubated with radiolabeled 18:3n-6, over 40% of the radioactivity was metabolized mainly to 20:4n-6 in liver slices, but evenly to 20:3n-6 and 20:4n-6 in kidney slices. There were no differences between the results from SHR and those from WKY. In WKY rats given an oral bolus of radiolabeled 18:3n-6, most of the radioactivity was recovered in the liver and significantly less in the kidney. In both tissues, the radioactivity was associated initially only with 18:3n-6 and later with its elongation product, 20:3n-6. These findings indicated that the kidney, although unable to metabolize 18:2n-6, could metabolize 18:3n-6 taken up from the circulation. The effectiveness of 18:3n-6, compared to 18:2n-6, as an anti-hypertensive agent may result from the provision of a post-delta 6-desaturation metabolite which can be directly converted to blood pressure-regulating eicosanoids in the kidney.

Animals↗
PubMed1994

Effects of dietary protein and cholesterol on phosphatidylcholine and phosphatidylethanolamine molecular species in mouse liver.

The present study examined the effects of two atherogenic factors, animal protein and cholesterol, on the distribution of fatty acids and the molecular species of major liver phospholipids in mice. Weanling mice were fed a semisynthetic diet supplemented with either casein or soy protein (20%, w/w) in the presence or absence of 0.5% cholesterol for 4 wk. Results from mouse liver showed that animal protein and, more so, dietary cholesterol modified the fatty acid profiles of the phospholipids. Animal protein had no significant effect on the concentration of lipids, but it altered the relative distribution and fatty acid profiles of the phospholipids, phosphatidylcholine and phosphatidylethanolamine. Dietary cholesterol, on the other hand, significantly increased the concentration of liver lipids, but it did not alter the relative distribution of phosphatidylcholine and phosphatidylethanolamine. In cholesterol-fed mice, the proportions of molecular species containing 18:2n-6 were increased, whereas those containing 20:4n-6 were decreased, indicating that dietary cholesterol suppressed linoleic acid metabolism. Since cholesterol feeding selectively decreased the ratio of 18:0/20:4n-6 in phosphatidylcholine, whereas it increased the 18:0/18:2n-6 ratio in phosphatidylethanolamine, this finding suggests that dietary cholesterol may affect the incorporation of fatty acids but not the rate of synthesis of phosphatidylcholine and phosphatidylethanolamine.

Animals↗
PubMed1994

Liver delta 5 and delta 6 desaturase activity differs among laboratory rat strains.

This study was designed to examine the variations among rat strains in hepatic fatty acid desaturase activities and to determine the correlations between the activities of these enzymes and the levels of each microsomal fatty acid. Wistar rats from two different sources as well as Long-Evans and Sprague-Dawley rats were selected to assess, under standard and identical experimental conditions, the liver delta 5 and delta 6 desaturase activities. Both desaturase activities were significantly reduced by 56% in Sprague-Dawley rats when compared to BB-Wistar control rats, whereas intermediate reduced values were detected in Wistar (CR) and Long-Evans strains. The activities of delta 5 and delta 6 desaturases were significantly and positively correlated with each other. However, no significant correlations were detected between either delta 5 or delta 6 desaturase activities and levels of any of their fatty acid substrates or any other of the major microsomal fatty acids. Fatty acid composition of microsomal total lipids showed strain dependency. A positive correlation was detected between the microsomal levels of the two major final products of both desaturases, namely 20:4n-6 and 22:6n-3. In general, the sum of n-3 or n-6 fatty acids but not the ratio of one to the other, varied among rat strains. The study demonstrated that delta 6 and delta 5 desaturase activities are strain-related. The data also suggested that (i) the desaturation activity should be measured and not predicted from the fatty acid composition and (ii) different rat strains should be used for lipid metabolic studies before conclusions are drawn for rats in general.

Animals↗
PubMed1994

The membrane hypothesis of schizophrenia.

The phospholipid structure of neuronal membranes is essential for normal functioning of the nervous system. Evidence is accumulating that phospholipid metabolism in both brain and red blood cells may be disturbed in schizophrenia. In particular, in patients with negative symptoms, levels of arachidonic acid and docosahexanoic acid in red blood cell membrane phospholipids are severely abnormal. The membrane hypothesis of schizophrenia may represent a new and fruitful paradigm for future research.

Brain↗
PubMed1994

A red cell membrane abnormality in a subgroup of schizophrenic patients: evidence for two diseases.

There are several reports of abnormalities in fatty acids in brain and blood phospholipids in schizophrenic patients. In order to see if the broad categories of negative and positive schizophrenia were linked to specific changes in fatty acids, an initial study was made of patients showing severe symptoms of these two types. Thirteen patients had persistent chronic negative symptoms of apathy and withdrawal while 12 patients had persistent positive symptoms of either thought disorder or hallucinations and delusions. The positive and negative groups were matched for length of history and drug exposure. Negative symptoms were associated with high levels of saturated fatty acids and low levels of long-chain unsaturates in red blood cell (RBC) membranes, while the positive symptom patients showed the opposite picture. In order to see if this bimodal distribution would be found in patients diagnosed as schizophrenic but without classification of symptoms, we examined frequency distribution curves for fatty acids in plasma and in RBC membranes in 68 individuals classified as schizophrenics and 259 normal individuals. A bimodal distribution was found for 20- and 22-carbon unsaturated fatty acids in RBC membranes from the schizophrenics; the same fatty acids in normal RBC membranes showed an unimodal distribution.

Adult↗
PubMed1994

Relationship between plasma essential fatty acids and smoking, serum lipids, blood pressure and haemostatic and rheological factors.

We aimed to determine whether levels of plasma fatty acids are correlated with other potential risk factors for cardiovascular disease, using a sample of patients from a cross-sectional survey of the general population, in the City of Edinburgh. 306 men and women aged 55-74 years of whom half had clinical evidence of arterial disease were tested. The main outcome measures were plasma fatty acids and potential risk factors for cardiovascular disease (age, sex, smoking, blood pressure, serum cholesterol, HDL cholesterol (HDL-C), triglycerides (TGs), lipid peroxides (LPx), plasma fibrinogen, von-Willebrand factor (vWf), beta-thromboglobulin (beta TG), cross-linked fibrin degradation products (FIBDP) and plasminogen activator inhibitor PAI). High levels of several known risk factors for cardiovascular diseases were associated with low levels of certain essential fatty acids. Eicosapentaenoic (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) were negatively associated with smoking and TG levels. High levels of certain haemostatic factors, including plasma fibrinogen, blood viscosity and LPx were also associated with low levels of EPA, DHA, AA and HDL-C. In conclusion, plasma fatty acids show strong correlations with many potential risk factors for cardiovascular disease, emphasising their possible importance in pathogenesis.

Aged↗
PubMed1994

Adrenic acid delta 4 desaturation and fatty acid composition in liver microsomes of spontaneously diabetic Wistar BB rats.

We examined the delta 4 (n-6) desaturation and the fatty acid composition of liver microsomes in the insulin-dependent spontaneously diabetic Wistar Bio-Breeding (BB) rat. The desaturation of adrenic acid to n-6 docosapentaenoic acid was decreased in the normo- and hyperglycemic diabetic rats. Insulin treatment with 1.0 IU. 100 g body weight-1 twice a day for 2 days restored the reduced activity during the hypoglycemic period. The pattern of responses was similar to that of linoleic acid delta 6 and dihomo-gamma-linolenic acid delta 5 desaturases, with a non-parallel relationship between the desaturation system and the glycemia. The microsomal fatty acid composition of BB rat liver reflected only partially to the delta 4 desaturation at different states of glycemia. Factors other than impaired desaturation system are involved in the fatty acid metabolism of spontaneously diabetic rats.

Animals↗
PubMed1994

Study of plasma and red cell phospholipid fatty acids in extrahepatic cholestatic jaundice.

The poor outcome in patients with extrahepatic cholestatic jaundice seems in some way related to reticuloendothelial dysfunction. Similar dysfunction can be caused by abnormal tissue phospholipid fatty acid patterns. Little is, however, known about such patterns in extrahepatic cholestatic jaundice. The phospholipid fatty acid patterns in 42 controls were compared with 42 patients with extrahepatic cholestatic jaundice. Many abnormalities were found. The general pattern was of a fall in polyunsaturated fatty acids and a rise in monounsaturated fatty acids, with a consequent fall in the double bond index (mean number of double bonds per fatty acid) showing an overall rise in saturation. All three major substrates for eicosanoid production were reduced in the jaundiced group. The changes seemed to be associated with jaundice itself, rather than the cause of the jaundice. The central roles of fatty acids in the determination of membrane function and in the provision of substrates of eicosanoid production, mean that these changes may explain some of the reticuloendothelial dysfunction found in extrahepatic cholestatic jaundice.

Adult↗
PubMed1994

Plasma essential fatty acids, cigarette smoking, and dietary antioxidants in peripheral arterial disease. A population-based case-control study.

The aim of this study was to determine the levels of plasma fatty acids in patients with peripheral arterial disease and in control subjects and to identify whether any risks of disease related to these differences were influenced by smoking and antioxidant intake. A random sample of 1592 men and women aged 55 to 74 years was selected from the general population (the Edinburgh Artery Study), from which 153 cases of peripheral arterial disease were identified by the presence of intermittent claudication and low ankle systolic pressures at rest and during reactive hyperemia; these were matched by age and sex to 153 control subjects with no evidence of cardiovascular disease. In 113 case and 122 control subjects, fatty acid levels were measured in three plasma fractions (triglyceride, cholesteryl ester, and phospholipid), and smoking habits and dietary antioxidant intake were determined by questionnaire. Arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid (DPA/n-3) were significantly lower in the cases than controls (P < .01). More case than control subjects were current or exsmokers (86% versus 50%; P < .001), and the case subjects had lower vitamin C intake (64.8 mg versus 71.1 mg; P < .05). By logistic regression adjustment for smoking and vitamin C intake, only DPA/n-3 (odds ratio, 0.19; P < .01) and arachidonic acid (odds ratio, 0.44; P < .05) remained significantly related to disease; only DPA/n-3 reduced the risk associated with smoking. We conclude that in subjects with peripheral arterial disease compared with healthy control subjects, the largest differences occurred in fatty acids of the n-3 series, particularly DPA/n-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Concentration-dependent effect of iron on gamma-linolenic acid toxicity in ZR-75-1 human breast tumor cells in culture.

Polyunsaturated fatty acids are cytotoxic to ZR-75-1 human breast tumor cells in culture. This effect may be potentiated by the simultaneous addition of iron. When cytotoxicity was measured in the presence of different concentrations of both gamma-linolenic acid and ferrous chloride there was an increase in cell death above concentrations of 9 microM and 0.05 microM, respectively. The potentiation of the effects of 18:3n-6 at low concentrations by the simultaneous addition of Fe(II) ions supports the contention that an alteration in the intracellular Fe(II)/Fe(III) ratio is necessary to promote autocatalytic lipid peroxidation.

Breast Neoplasms↗
PubMed1993

Effects of saturated fatty acids on n-6 fatty acid metabolism in cultured human monocyte-like cells (U937).

Effects of supplementation of saturated fatty acids (16:0 and 18:0) on metabolism of the cytotoxic n-6 fatty acids in cultured human monocyte-like cells (U937) have been examined. U937 cells were incubated in 5% delipidated fetal bovine serum containing 16:0 and 18:0. Supplementation of either 16:0 or 18:0 has no significant effect on the uptake of 18:2n-6 and 18:3n-6. However, addition of 16:0 to the medium increased whereas 18:0 suppressed the cytotoxic effects of 18:2n-6 and 18:3n-6. In addition, 16:0 supplementation reduced the incorporation of n-6 fatty acids in cellular phospholipid fraction, and enhanced the metabolism of n-6 fatty acids, particularly the conversion of 20:3n-6 to 20:4n-6 in U937 cells. Results with microsomes prepared from U937 cells also showed that 16:0 supplementation increased the delta 5 desaturase activity. This may be related in part to an increase in the availability of 20:3n-6, since results obtained in a separate study have shown that 16:0 competed with 20:3n-6 for incorporation into the phospholipid molecule at sn-2 position. Increasing the availability and formation of long chain n-6 fatty acids, which are cytotoxic, might also be responsible for increasing cytotoxicity of 16:0 supplementation.

Cell Survival↗