Parent Fatty Acids Research Articles

The role of methyl-linoleic acid epoxide and diol metabolites in the amplified toxicity of linoleic acid and polychlorinated biphenyls to vascular endothelial cells.

Selected dietary lipids may increase the atherogenic effects of environmental chemicals, such as polychlorinated biphenyls (PCBs), by cross-amplifying mechanisms leading to dysfunction of the vascular endothelium. We have shown previously that the omega-6 parent fatty acid, linoleic acid, or 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an aryl hydrocarbon (Ah) receptor agonist, independently can cause disruption of endothelial barrier function. Furthermore, cellular enrichment with linoleic acid can amplify PCB-induced endothelial cell dysfunction. We hypothesize that the amplified toxicity of linoleic acid and PCBs to endothelial cells could be mediated in part by cytotoxic epoxide metabolites of linoleic acid called leukotoxins (LTX) or their diol derivatives (LTXD). Exposure to LTXD resulted in a dose-dependent increase in albumin transfer across endothelial cell monolayers, whereas this disruption of endothelial barrier function was observed only at a high concentration of LTX. Pretreatment with the cytosolic epoxide hydrolase inhibitor 1-cyclohexyl-3-dodecyl urea partially protected against the observed LTX-induced endothelial dysfunction. Endothelial cell activation mediated by LTX and/or LTXD also enhanced nuclear translocation of the transcription factor NF-kappa B and gene expression of the inflammatory cytokine IL-6. Inhibiting cytosolic epoxide hydrolase decreased the LTX-mediated induction of both NF-kappa B and the IL-6 gene, whereas the antioxidant vitamin E did not block LTX-induced endothelial cell activation. Most importantly, inhibition of cytosolic epoxide hydrolase blocked both linoleic acid-induced cytotoxicity, as well as the additive toxicity of linoleic acid plus PCB 77 to endothelial cells. Interestingly, cellular uptake and accumulation of linoleic acid was markedly enhanced in the presence of PCB 77. These data suggest that cytotoxic epoxide metabolites of linoleic acid play a critical role in linoleic acid-induced endothelial cell dysfunction. Furthermore, the severe toxicity of PCBs in the presence of linoleic acid may be due in part to the generation of epoxide and diol metabolites. These findings have implications in understanding interactive mechanisms of how dietary fats can modulate dysfunction of the vascular endothelium mediated by certain environmental contaminants.

Monohydroxylation and esterification as determinants of the effects of cis- and trans-9-octadecenoic acids on the permeation of hydrocortisone and 5-fluorouracil across hairless mouse skin in vitro

The effects of cis-9-octadecenoic acid (oleic acid) and of a group of chemically related cis- (ricinoleic acid) and trans- (ricinelaidic acid) 12-monohydroxylated derivatives and their corresponding ethyl and methyl esters on the skin permeation of model hydrophobic (hydrocortisone, log K=1.61) and hydrophilic (5-fluorouracil, log K=−0.89) drugs was investigated in vitro using excised hairless mouse skin. Drug solutions were prepared in propylene glycol, with and without the addition of a fatty acid to a level of 5%. Whereas the addition of oleic acid markedly enhanced the transdermal flux of both drugs relative to a sample in propylene glycol alone (hydrocortisone∼1800-fold; 5-fluorouracil∼330-fold), that of a cis- or trans-12-monohydroxylated analog of oleic acid resulted in only a small increase (1.4–2.7-fold for hydrocortisone; 4.4–6.6-fold for 5-fluorouracil). On the other hand, the methyl and ethyl esters of cis- and trans-12-hydroxy-9-octadecenoic acid exerted a much greater enhancing effect (327–720-fold for hydrocortisone, 42–74-fold for 5-fluorouracil) than the corresponding parent fatty acids. Furthermore, whereas the ethyl esters were found to have a greater effect on the skin permeation of hydrocortisone than the methyl esters, the reverse was true with regards to 5-fluorouracil. Additionally, the esters of trans-12-hydroxy-9-octadecenoic acid promoted permeation to an extent comparable to that achieved with their cis-counterparts.

The Significance of Alpha-Linolenic Acid for Humans.

The omega 3 polyunsaturated fatty acids have had a major impact on thinking in medicine in the last twenty-five years. The parent fatty acid in the omega 3 fatty acid family is alpha-linolenic acid (ALA) which is an essential fatty acid found in high concentrations in certain plant oils, such as flaxseed oil, walnut oil and canola oil. Several longer chain or derived omega 3 fatty acids are formed in the body from ALA, including eicosapentaenoic acid, EPA, decosapentaenoic acid and docosahexaenoic acid, DHA. Dietary sources of these longer-chain fatty acids are fish, fish oils and from other marine organisms. DHA is specifically localised in the retina and the brain in humans and other mammals where it has a primary role via effects on membrane order (fluidity), the activity of membrane-bound enzymes, ion channels and signal transduction. For many years, ALA has been considered to be important only as a precursor of these longer chain compounds, however it is now recognaised that ALA is metabolished by other pathways which may be quantiatively more important than the formation of DHA. For example, ALA is extensively β-oxidised in mammals including humans, especially on diets rich in polyunsaturated fatty acids. ALA appears to play an important role in the nervous system (carbon recycling) for the synthesis of saturated and monounsaturated fatty acids and cholesterol, with estimates of the proportion of ALA being matabolised via this pathway being several fold greater than that to DHA. Furthermore, recent studies have indicated that ALA is deposited in the skin of small mammals and may also play a role in fur. Since ALA is extensively metabolised via these pathways (β-oxidation, carbon recycling and deposition in skin/fur) and is subject to competitive inhibition from linoleic acid in metabolism via the delta-6 desaturase, it is not surprising tha dietary DHA is substantially more effctive than an equivalent dose of dietary ALA in maintaining neural DHA levels. Despite the limited efficiency of DHA formation from ALA, it is clear that certain tissues possess the capacity to synthesise DHA at rates greater than other tissues. The brain, retina and reproductive tissue may be able to synthesis sufficient DHA to meet the DHA demands of these tissues, although in infants at the peak of brain growth and DHA deposition, a dietary supply of DHA (as in milk) may be important to maintain the brain DHA level. In plants, ALA is a substrate for lipoxygenase enzymes leading to the poduction of bioactive hydroxy compounds. This information might provide a clue to other routes of ALA metabolism in mammals. It is concluded that it may no longer be appropriate to consider the function for ALA to be solely a precursor of EPA and DHA.

Final Report on the Safety Assessment of Cocoyl Sarcosine, Lauroyl Sarcosine, Myristoyl Sarcosine, Oleoyl Sarcosine, Stearoyl Sarcosine, Sodium Cocoyl Sarcosinate, Sodium Lauroyl Sarcosinate, Sodium Myristoyl Sarcosinate, Ammonium Cocoyl Sarcosinate, and Ammonium Lauroyl Sarcosinate

This safety assessment addresses cosmetic ingredients that are N-acyl derivatives of sarcosine and are generally referred to as acyl sarcosines, and those that are salts, known generally as acyl sar-cosinates. Previous assessments have addressed the safety of each of the fatty acids that appear in these acyl sarcosines and sarcosinates (Coconut Acid, Oleic Acid, Lauric Acid, and Myristic Acid). In each case the fatty acid was either safe for use or safe as used in cosmetic formulations. Acyl sarcosines are considered modified fatty acids with greater solubility and increased acidity of the carboxylic acid group compared to the parent fatty acid. They are used in a large number of cosmetic formulations as hair-conditioning agents and surfactant-cleansing agents. In soaps, concentrations are reported to be as high as 12.9%. These ingredients have low oral toxicity in rats. Although cytotoxic to Chinese hamster cells in culture, acyl sarcosines and sarcosinates are not mutagenic in those cells, nor in bacterial cells in culture. Carcinogenicity data were not available. These ingredients are nonirritating and nonsen-sitizing to animal and human skin, although they can enhance the penetration of other ingredients through the skin. For that reason, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern (e.g., HC Yellow No. 4, Disperse Yellow 3). Because sarcosine can be nitrosated to form N-nitrososarcosine, a known animal carcinogen, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. With the above caveat, and based on the available data, it was concluded that these acyl sarcosines and sarcosinates are safe as used in rinse-off products. They may be safely used in leave-on products at concentrations up to 5%, the highest concentration tested in clinical irritation and sensitization studies. Oleoyl Sarcosine is used as a corrosion inhibitor in some aerosol products, at extremely low concentrations. In this circumstance, the ingredient is not being used as a cosmetic ingredient and this report is not intended to limit that use. Because of the absence of data on inhalation toxicity, however, it was concluded that the available data were not sufficient to support the safety of acyl sarcosines and sarcosinates as cosmetic ingredients in products where they are likely to be inhaled.

Final Report on the Safety Assessment of Cocoyl Sarcosine, Lauroyl Sarcosine, Myristoyl Sarcosine, Oleoyl Sarcosine, Stearoyl Sarcosine, Sodium Cocoyl Sarcosinate, Sodium Lauroyl Sarcosinate, Sodium Myristoyl Sarcosinate, Ammonium Cocoyl Sarcosinate, and Ammonium Lauroyl Sarcosinate

This safety assessment addresses cosmetic ingredients that are N-acyl derivatives of sarcosine and are generally referred to as acyl sarcosines, and those that are salts, known generally as acyl sar-cosinates. Previous assessments have addressed the safety of each of the fatty acids that appear in these acyl sarcosines and sarcosinates (Coconut Acid, Oleic Acid, Lauric Acid, and Myristic Acid). In each case the fatty acid was either safe for use or safe as used in cosmetic formulations. Acyl sarcosines are considered modified fatty acids with greater solubility and increased acidity of the carboxylic acid group compared to the parent fatty acid. They are used in a large number of cosmetic formulations as hair-conditioning agents and surfactant-cleansing agents. In soaps, concentrations are reported to be as high as 12.9%. These ingredients have low oral toxicity in rats. Although cytotoxic to Chinese hamster cells in culture, acyl sarcosines and sarcosinates are not mutagenic in those cells, nor in bacterial cells in culture. Carcinogenicity data were not available. These ingredients are nonirritating and nonsen-sitizing to animal and human skin, although they can enhance the penetration of other ingredients through the skin. For that reason, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern (e.g., HC Yellow No. 4, Disperse Yellow 3). Because sarcosine can be nitrosated to form N-nitrososarcosine, a known animal carcinogen, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. With the above caveat, and based on the available data, it was concluded that these acyl sarcosines and sarcosinates are safe as used in rinse-off products. They may be safely used in leave-on products at concentrations up to 5%, the highest concentration tested in clinical irritation and sensitization studies. Oleoyl Sarcosine is used as a corrosion inhibitor in some aerosol products, at extremely low concentrations. In this circumstance, the ingredient is not being used as a cosmetic ingredient and this report is not intended to limit that use. Because of the absence of data on inhalation toxicity, however, it was concluded that the available data were not sufficient to support the safety of acyl sarcosines and sarcosinates as cosmetic ingredients in products where they are likely to be inhaled.

Perfluoroalkyl ketones: novel derivatization products for the sensitive determination of fatty acids by gas chromatography/mass spectrometry in electron impact and negative chemical ionization modes

Analytically useful pentafluoro ketone derivatives of fatty acids are described. The gas chromatographic/mass spectrometric characteristics of these new derivatives are compared with those of methyl, trimethylsilyl and pentafluorobenzyl esters. Pentafluoro ketones exhibit excellent chromatographic properties and significantly shorter chromatographic retention times than these other esters. The electron impact mass spectra of these new compounds show informative acylium ions, whose intensity decreases with the degree of unsaturation of the parent fatty acid. The formation of strong and informative fragment ions in negative chemical ionization (CH(4)) mass spectra of pentafluoro ketone derivatives allows the detection and the characterization (length of the chain and number of double bonds) of fatty acids at trace levels (femtomole), even in the case of polyunsaturated compounds. The scope and limitations of this new derivatization technique are also discussed.

Phospholipid incorporation and metabolic conversion of n-3 polyunsaturated fatty acids in the Y79 retinoblastoma cell line.

The metabolic conversion of n-3 fatty acids was studied in the human Y79 retinoblastoma cell line. Cultured cells were exposed to increasing concentrations of either 18:3n-3, 22:5n-3, or 22:6n-3, and their phospholipid fatty acid composition was analyzed after 72 hr. Cells internalized the supplemental fatty acids and proceeded to their metabolic conversion. Supplemental 22:6n-3 was directly esterified into cell phospholipids, at levels typical for normal neural retinas (41% by weight of phosphatidylethanolamine fatty acids, and 24% of phosphatidylcholine fatty acids). In contrast, 18:3n-3 was mainly converted to 20:5n-3 and 22:5n-3, both of which appeared in cell phospholipids after exposure to low external concentrations of 18:3n-3 (10 microg/ml). Y79 cells can proceed to the metabolic conversion of 18:3n-3 through elongation and Delta6- and Delta5-desaturation. When cells were exposed to high external concentrations of 18:3n-3 (30 microg/ml), the supplemental fatty acid was directly incorporated, and its relative content increased in both phospholipid classes to the detriment of all other n-3 fatty acids. Cells cultured in the presence of 22:5n-3 did not incorporate 22:6n-3 into their phospholipids but did incorporate 20:5n-3 and 22:5n-3. The data suggest that Y79 cells can proceed to the microsomal steps of n-3 metabolism, involving elongation, desaturation, and chain shortening of 22C fatty acids. Although Y79 cells avidly used supplemental 22:6n-3 for phospholipid incorporation at levels typical for normal photoreceptor cells, they failed to match such levels through metabolic conversion of n-3 parent fatty acids. The terminal step of the very long-chain polyunsaturated fatty acid synthesis, consisting in Delta6-desaturation followed by peroxisomal chain shortening of 24C-fatty acids, could be rate-limiting in Y79 cells.

Perfluoroalkyl ketones: novel derivatization products for the sensitive determination of fatty acids by gas chromatography/mass spectrometry in electron impact and negative chemical ionization modes.

Analytically useful pentafluoro ketone derivatives of fatty acids are described. The gas chromatographic/mass spectrometric characteristics of these new derivatives are compared with those of methyl, trimethylsilyl and pentafluorobenzyl esters. Pentafluoro ketones exhibit excellent chromatographic properties and significantly shorter chromatographic retention times than these other esters. The electron impact mass spectra of these new compounds show informative acylium ions, whose intensity decreases with the degree of unsaturation of the parent fatty acid. The formation of strong and informative fragment ions in negative chemical ionization (CH(4)) mass spectra of pentafluoro ketone derivatives allows the detection and the characterization (length of the chain and number of double bonds) of fatty acids at trace levels (femtomole), even in the case of polyunsaturated compounds. The scope and limitations of this new derivatization technique are also discussed.

Fatty acid composition of human milk in Kuwaiti mothers

Kuwaiti diet is exceptionally rich in fat, carbohydrates and proteins. In addition, subjects in Kuwait are exposed to extreme heat and sun light. Fatty acid profiles of human milk obtained from 19 full breast feeding Kuwaiti mothers were analyzed. Dietary patterns for individual mothers were determined by 24 h dietary recall and food frequency questionnaire. The fatty acid content of human milk was affected by the diet consumed by the lactating mother. The content of long chain polyunsaturated fatty acids (LCP) in human milk lipids did not correlate with their parent fatty acids like linoleic and α-linolenic acids. However the human milk LCP were related to the of content of LCP in the maternal diet. Mothers reporting a high fish consumption showed significant amounts of C22:6, ω3 and C20:5, ω3 fatty acids. As a general conclusion, breast milk produced by a well nourished mother is better suited to meet the lipid requirements of infants.

Essential fatty acid requirements of vegetarians in pregnancy, lactation, and infancy

Long-chain polyunsaturated fatty acids (LCPUFAs) derived from linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids are required for the normal development of the retina and central nervous system, but the extent to which they can be synthesized from the parent fatty acids is debated. Consuming LCPUFAs markedly increases their proportions in tissue lipids compared with their parent fatty acids. Thus, it has been argued that LCPUFAs must be supplied in the diet. LCPUFAs are generally absent from plant foods, thus it is important find out how essential fatty acid requirements are met by vegetarians. A developing fetus obtains LCPUFAs via selective uptake from its mother's plasma and LCPUFAs are present in the breast milk of vegetarians. There is no evidence that the capacity to synthesize LCPUFAs is limited in vegetarians. However, there are greater proportions of n-6 LCPUFAs and lower proportions of n-3 LCPUFAs in vegetarians compared with omnivores. This difference is probably a consequence of the selection of foods by vegetarians with high amounts of linoleic acid. Although lower concentrations of docosahexaenoic acid (22:6n-3; DHA) have been observed in blood and artery phospholipids of infants of vegetarians, it is uncertain whether their brain lipids contain lower proportions of DHA than do those of infants of omnivores. On the basis of experiments in primates that showed altered visual function with a high ratio of linoleic acid to alpha-linolenic acid, it would be prudent to recommend diets with a ratio between 4:1 and 10:1 in vegetarians and that excessive intakes of linoleic acid be avoided.

Effects of pregnancy-induced hypertension on the essential fatty acid statuses of Ecuadorian and Dutch women

Objective: Among white Dutch women pregnancy-induced hypertension was shown to be associated with elevated levels of the long-chain polyenes of 18:2n-6 and 18:3n-3 in combination with reduced levels of those parent essential fatty acids. This observation suggested an enhanced desaturation and elongation of the parent fatty acids. This study was performed to investigate whether this phenomenon also occurs under completely different nutritional and geographic conditions. Study Design: Plasma fatty acids of primiparous Mestizo Ecuadorian women with uncomplicated pregnancies and with pregnancy-induced hypertension were assessed at delivery and compared with similar data from white Dutch women. Neonatal values, as determined in umbilical plasma and umbilical vessel walls, were also compared. Results: In contrast to the pattern seen among white mothers, pregnancy-induced hypertension did not increase the long-chain polyene status of Mestizo mothers. Despite the absence of this compensatory mechanism, long-chain polyene status was not compromised in Mestizo neonates born after pregnancy-induced hypertension. Conclusion: Additional mechanisms may be active in maintaining the long-chain polyene status of neonates born after pregnancy-induced hypertension. (Am J Obstet Gynecol 1999;180:1185-90.)

Synthesis of hydroperoxide and perketal derivatives of polyunsaturated fatty acids as potential antimalarial agents

Hydroperoxide derivatives of β-oxa-substituted polyunsaturated fatty acids were prepared by 15-lipoxygenase catalysed oxidation and perketal derivatives of fatty acid hydroperoxides were synthesized. The perketals are more stable than their parent fatty acid hydroperoxides, but less active as antimalarial agents in the in vitro growth inhibition of Plasmodium falciparum.

Stereochemical aspects of fatty acid oxidation: hydroperoxide isomerases.

Lipoxygenases catalyze dioxygenation of polyunsaturated fatty acids to produce fatty-acid hydroperoxides. The reaction involves initial stereospecific abstraction of a hydrogen atom from a bis-allylic methylene group followed by antarafacial attack by dioxygen at one of the terminal carbon atoms of the pentadienyl radical. 8(R)-Dioxygenase, recently discovered in the fungus Gaeumannomyces graminis, catalyzes formation of 8-hydroperoxy derivatives of linoleic and oleic acids by abstracting one hydrogen from C-8 and inserting dioxygen at the same carbon atom. Isotope-labeling studies show that the configuration at C-8 is inverted during this process. The fungus Saprolegnia parasitica, a fish parasite, contains an omega 6-lipoxygenase and an epoxy alcohol synthase. The latter enzyme catalyzes isomerization of fatty acid hydroperoxides into alpha,beta- and gamma,delta-epoxy alcohols. Experiments with 18O-labelled hydroperoxides demonstrate that the hydroperoxide --> epoxy alcohol conversion consists of intramolecular transfer of the terminal hydroperoxide oxygen to either of the two conjugated double bonds. The reactions proceed with retention of geometrical configuration, i.e. epoxidation of the alpha,beta (E) and gamma,delta (Z) double bonds of the parent fatty acid hydroperoxide gives rise to trans and cis epoxides, respectively. G. graminis, as well as the marine red alga Gracilariopsis lemaneiformis, contain vicinal diol synthases that catalyze isomerization of fatty-acid hydroperoxides into vicinal dihydroxy fatty acids. Studies using 18O-labelled hydroperoxides show that the hydroperoxide --> diol conversions occur by intramolecular transfer of the terminal hydroperoxide oxygen to the vicinal methylene group. Experiments with stereospecifically deuteriated fatty-acid hydroperoxides demonstrate that the intramolecular hydroxylations catalyzed by the two vicinal diol synthases proceed with retention of absolute configuration of the carbon hydroxylated.

Methyl-branched fatty acids and their biosynthesis in the housefly, Musca domestica L. (Diptera: Muscidae)

Eighteen methyl-branched fatty acids from the housfly, Musca domestica were identified by gas chromatography-mass spectrometry after reduction to the corresponding hydrocarbons. A deuterium was inserted on what was the carboxyl carbon and the straight chain components were removed by molecular sieve. The deuterium allowed the mass spectral determination of the methyl branch position with respect to the carboxyl end of the parent fatty acid methyl-branched fatty acids were characterized as n-2, n-3, n-4, n-5, n-6, n-7, n-8, and n-9 monomethyl fatty acids of 15—19 carbons and a n-3, 7 dimethyl fatty acid of 18 total carbons. These methyl-branched fatty acids have similar branching patterns and are presumed to the precursors to the methyl-branched hydrocarbons, some of which function as an arrestant in the female sex pheromone. With increasing concentrations of methylmalonyl-CoA, its incorporation into methyl-branched fatty acids increased in both day 1 and day 4 males and females using both microsomal and soluble fatty acid synthases (FAS). Methylmalonyl-CoA inhibited both the soluble and microsomal FAS in a competitive manner. The data on the incorporation of methylmalonyl-CoA into methyl-branched fatty acids by day 1 and day 4 males and females indicate that the regulation of methyl-branched hydrocarbon synthesis does not reside at the level of fatty acid synthesis, but must occur during the process of the fatty acyl-CoA elongation or reductive conversion of very long chain fatty acyl-CoAs to hydrocarbons.

In vitro activation of mouse skin protein kinase C by fatty acids and their hydroxylated metabolites

To understand how dietary fatty acids differentially modulate mouse skin tumorigenesis, the ability of specific fatty acids and their derivatives to activate murine epidermal protein kinase C (PKC) in vitro was investigated. Total PKC from untreated female SSIN mouse skin was partially purified and incubated with specific fatty acids at concentrations up to 300 microM in the presence of Ca2+ and phosphatidylserine. The cis-unsaturated fatty acids tested, ranging from 16:1 to 22:6, stimulated PKC activity in a similar dose-dependent manner with an approximate threefold maximum increase over control. Neither the number of cis-double bonds nor the chainlength of these fatty acids affected their relative ability to activate PKC. trans-Fatty acids, with the exception of linoelaidic acid (t,t-18:2n-6), exhibited about half of the potency of their corresponding cis-isomers in stimulating PKC at the plateau concentration (200 microM) or lower. Substitutions close to the double bond on cis-fatty acids abolished their ability to activate PKC. The hydroxylated metabolites of arachidonic acid (20:4n-6) and linoleic acid (c,c-18:2n-6), i.e., the hydroxyeicosatetraenoic acids (HETE) and hydroxyoctadecadienoic acids (HODE), also activated mouse skin PKC in vitro, but only about half as effectively as did the respective parent fatty acids. The results suggest that both hydroxyl substitution and trans-configuration of HETE and HODE are responsible for their reduced ability to activate PKC. Overall the data suggests that the reduced skin tumor yield observed in mice fed diets high in c,c-18:2n-6 is not likely to be due to differences in the ability of c,c-18:2n-6 or 20:4n-6, or their metabolites, to activate PKC.

Lipoxygenase stimulating effects of hydroxylated docosahexaenoates produced by human platelets

Human platelet suspensions are capable of lipoxygenating docosahexaenoic acid (22:6n3) to an 11(S)-OH-, 14(S)-OH- or 17(S)-OH-22:6n3. The structure and stereochemical purity of these derivatives were confirmed by GC/MS and chiral phase LC analysis. The purified OH-22:6n3 positional isomers which are formed by human platelets were capable of inducing a concentration-dependent contractile response in the guinea-pig lung parenchymal strip at sub-micromolar concentrations. OH-22:6n3 may act in part through stimulation of leukotriene (LT) production as an increase in peptidyl-LT levels (LTC 4, LTD 4 and LTE 4) occurred during the OH-22:6n3-induced contraction in this preparation. Both specific lipoxygenase inhibitors (caffeic acid, 20 uM and NDGA, 50 uM) and a LT receptor antagonist (FPL55712, 20 uM) significantly inhibited the contractile response. Moreover, the OH-22:6n3 positional isomers induced a concentration-dependent increase in LTB 4 and LTC 4 production in the guinea-pig chopped lung preparation. Other hydroxylated fatty acids and parent fatty acids which were tested (12-OH-20:4n6, 5-OH-20:4n6, 12-OH-20:5n3, 20:5n3 and 22:6n3) did not significantly contract this airway smooth muscle preparation or alter LT production. The hydroxylated 22:6n3 metabolites may modulate airway smooth muscle function in part through the release of peptidyl-LTs from the guinea-pig lung.

Fungal strategies for detoxification of medium chain fatty acids

Fungi can degrade free fatty acids and triacylglycerols to provide a carbon and energy source. Medium chain fatty acids (those with a carbon length between six and 12 carbon atoms) are relatively uncommon. They are found in three oils of commercial importance—coconut, palm kernel and butter. The ability of fungi to convert medium chain fatty acids or triacylglycerols containing these acids to methyl ketones one carbon atom less has been known for a long time. Five genera can undertake these bioconversions— Aspergillus and Penicillium, and their corresponding teleomorphic genera Trichoderma, Cladosporium and Fusarium. Medium chain fatty acids inhibit fungal growth. The degree of inhibition depends on the concentration of the un-ionised acids. A number of fungal bioconversions of medium chain fatty acids can occur leading to the production of volatile metabolites. These include a partial β-oxidation to give the methyl ketone one carbon atom less than the parent fatty acid, reduction of the ketone to give the secondary alcohol, hydroxylation of the ketone to give a mono-hydroxy ketone, esterification and decarboxylation. It is suggested that the production of these volatile metabolites is a fungal strategy to eliminate metabolites which would otherwise be toxic.

Chlorohydrin formation from unsaturated fatty acids reacted with hypochlorous acid

Stimulated neutrophils produce hypochlorous acid (HOCl) via the myeloperoxidase-catalyzed reaction of hydrogen peroxide with chloride. The reactions of HOCl with oleic, linoleic, and arachidonic acids both as free fatty acids or bound in phosphatidylcholine have been studied. The products were identified by gas chromatography-mass spectrometry of the methylated and trimethylsilylated derivatives. Oleic acid was converted to the two 9,10-chlorohydrin isomers in near stoichiometric yield. Linoleic acid, at low HOCl:fatty acid ratios, yielded predominantly a mixture of the four possible monochlorohydrin isomers. Bischlorohydrins were also formed, in increasing amounts at higher HOCl concentrations. Arachidonic acid gave a complex mixture of mono- and bischlorohydrins, the relative proportions depending on the amount of HOCl added. Linoleic acid appears to be slightly more reactive than oleic acid with HOCl. Reactions of oleic and linoleic acids with myeloperoxidase, hydrogen peroxide, and chloride gave chlorohydrin products identical to those with HOCl. Lipid chlorohydrins have received little attention as products of reactions of neutrophil oxidants. They are more polar than the parent fatty acids, and if formed in cell membranes could cause disruption to membrane structure. Since cellular targets for HOCl appear to be membrane constituents, chlorohydrin formation from unsaturated lipids could be significant in neutrophil-mediated cytotoxicity.

Is There a Rational Use for n-3 Fatty Acids (Fish Oils) in Clinical Medicine?

double bond at the third position from the methyl end of the molecule (fig. I). The parent fatty acid in this family, a-linolenic acid (l8:3n-3), may be elongated and desaturated to eicosapentaenoic acid (EPA) [20:5n-3] and docosahexaenoic acid (DHA) [22:6n-3], although it is only poorly converted to the more polyunsaturated and desaturated n-3 fatty acids in humans (Bjerve 1989;Dyerberg et al. 1980; Renaud & Nordey 1983). [In the formulae for the fatty acids the first number gives the number of carbon atoms in the fatty acid molecule; the second digit indicates the number of double bonds; n (or omega) indicates the position of the first double 1. n-B Fatty Acids: What are They? Where are They? Do We Need Them? Although experimental studies in animals provided some evidence for an anti thrombotic effect of dietary n-3 fatty acids (Nordey 1965; Nordey et al. 1968), it was the pioneering work of Dyerberg et al. (1975, 1978) in Greenland Eskimos that introduced these fatty acids to clinical medicine, During the last decade it has been reported that the n-3 fatty acids have a wide range of important biological and physiological effects in humans. Despite this, the n-3 fatty acids have not previously been considered an essential nutrient, and only recently have international and national dietary recommendations even included requirements for n3 fatty acids. In 1982, Holman et al. reported alinolenic acid deficiency in a 6-year-old girl who had been treated with a formula diet low in n-3 fatty acids. The girl had visual and cerebral disturbances that disappeared rapidly after supplementation with these fatty acids. More recently, Bjerve (1989) has reported 9 patients with n-3 fatty acid deficiency. All 9 patients had been hospitalised for several years due to severe brain damage which necessitated long term gastric tube feeding. Dietary supply of n-3 fatty acids corrected biochemical deviations and clinical symptoms related to n-3 fatty acid deficiency.

The effect of temperature, water activity and sorbic acid on ketone rancidity produced by Penicillium crustosum Thom in coconut and palm kernel oils

In a model system medium‐chain fatty acids (MCFA) C6–C12 in coconut and palm kernel oil are converted to methyl ketones, one carbon atom less than the parent fatty acids, by two strains of Penicillium crustosum Thom. Conversion rates of up to 32% were seen for decanoic acid at 25°C. The optimum temperature for ketone production was 25°C in liquid suspension culture. Coconut oil contains 3.23 mmol/g MCFAs compared with 2.34 mmol/g for palm kernel oil. Coconut oil is more prone to fungal spoilage (growth and ketone production) than palm kernel oil. The main end product of fermentation was 2‐undecanone reflecting the high concentration of dodecanoic acid in the substrates. Ketonic rancidity is fungal engendered. The reaction can be controlled by reducing the temperature (4°C), reducing the water activity (0.91) or by addition of sorbic acid (20 mmol/l).