Arachidonic acid deficiency

Holman RT, Johnson SB, Gerrard JM, et al. Arachidonic acid deficiency in streptozotocin-induced diabetes. Proc Natl Acad Sci USA 1983 80 2375-2379. 

Approaches other than the use of pharmacological inhibitors have also been tried. Dietary manipulations leading to essential fatty acid deficiency and various drug trials have led to inconclusive results. Cook and co-workers demonstrated decreased mortality from endotoxin shock in rats raised on an essential fatty acid-deficient diet ". Although the decreased mortality was associated with a failure of plasma TxB levels to rise after endotoxin, one cannot conclude that thromboxane was instrumental in causing this syndrome since arachidonic acid deficiency may affect other metabolic pathways and... 

The perturbation of the incorporation of linoleic add metabolites into mammary gland lipids by CLA metabolism may lead to the hypothesis that CLA is able to create a mild arachidonic acid deficiency condition, in particular in the mammary tissue which is composed mainly of neutral lipids. In fact, because CLA and some of its metabolites are preferentially incorporated into neutral lipids (15), unlike linoleic acid, which is instead incorporated mainly into phospholipids, the preponderance of neutral lipids in the mammary tissue renders the competition between these two fatty acids more favorable toward CLA. It has been demonstrated that mammary tumorigenesis requires essential fatty acids, and eicosanoid inhibitors are able to reduce tumor incidence in experimental models (22). CLA, likely by decreasing the supply of arachidonic acid and inhibiting eicosanoid formation through its metabolites, may counteract arachidonic acid-derived eicosanoid action. Because the decrease of arachidonic acid, CLA metabolite incorporation, TEB density, and tumor incidence correlated with the (XA dietary intake, we can speculate that TEB density could also be modulated by eicosanoids. More data are required, however, to substantiate this hypothesis and to identify which eicosanoid(s) may be responsible for such effects. 

Prostaglandins arise from unsaturated C20 carboxylic acids such as arachidonic acid (see Table 26 1) Mammals cannot biosynthesize arachidonic acid directly They obtain Imoleic acid (Table 26 1) from vegetable oils m their diet and extend the car bon chain of Imoleic acid from 18 to 20 carbons while introducing two more double bonds Lmoleic acid is said to be an essential fatty acid, forming part of the dietary requirement of mammals Animals fed on diets that are deficient m Imoleic acid grow poorly and suffer a number of other disorders some of which are reversed on feed mg them vegetable oils rich m Imoleic acid and other polyunsaturated fatty acids One function of these substances is to provide the raw materials for prostaglandin biosynthesis... 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Rats fed a purified nonlipid diet containing vitamins A and D exhibit a reduced growth rate and reproductive deficiency which may be cured by the addition of linoleic, a-linolenic, and arachidonic acids to the diet. These fatty acids are found in high concentrations in vegetable oils (Table 14-2) and in small amounts in animal carcasses. These essential fatty acids are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation (see below), and they also have various other functions which are less well defined. Essential fatty acids are found in the stmctural lipids of the cell, often in the 2 position of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane. 

The essential fatty acids in humans are linoleic acid (C-18 2 N-6) and a-linolenic acid (C18 3 N-3). Arachidonic acid (C20 4 N-6) is also essential but can be synthesized from linoleic acid. Administration of 2% to 4% of total daily calories as linoleic acid should be adequate to prevent essential fatty acid deficiency in adults (e.g., infusion of 500 mL of 20% intravenous lipid emulsion once weekly).7 Biochemical evidence of essential fatty acid deficiency can develop in about 2 to 4 weeks in adult patients receiving lipid-free PN, and clinical manifestations generally appear after an additional... 

Essential fatty acid deficiency Deficiency of linoleic acid, linolenic acid, and/or arachidonic acid, characterized by hair loss, thinning of skin, and skin desquamation. Long-chain fatty acids include trienes (containing three double-bonds [e.g., 5,8,11-eicosatrienoic acid, or Mead acid trienoic acids) and tetraenes (containing four doublebonds [e.g., arachidonic acid]). Biochemical evidence of essential fatty acid deficiency includes a trieneitetraene ratio greater than 0.4 and low linoleic or arachidonic acid plasma concentrations. 

The second major breakthrough in understanding the defect in CGD neutrophils came through the development of assays in which the NADPH oxidase can be activated in a cell-free system in vitro ( 5.3.2.3). In these systems, activation of the oxidase can be achieved by the addition of cytoplasm to plasma membranes in the presence of NADPH and arachidonic acid (or SDS or related substances). Interestingly, the oxidase cannot be activated in these cell-free systems using extracts from CGD neutrophils however, cytosol and plasma membranes from normal and CGD neutrophils may be mixed, and in most cases activity is restored if the correct mixing pattern is used. For example, as may be predicted, in X-linked CGD it is the membranes that are defective (because the cytochrome b is deficient), whereas in autosomal recessive CGD the cytosol is defective in the cell-free system. 

The last essential dietary components to which we will refer and which were also discovered through feeding experiments with rats, are certain unsaturated fatty acids identified as linoleic, linolenic, and arachidonic acids by Burr and Burr in 1930. The acids are required for the formation of complex lipids which are essential in membranes for the maintenance of their fluidity (Chapter 9). Deficiencies lead to a dermatitis which does not respond to additional B vitamin supplements or to oleic acid. 

A functional method for detection depends upon competition for the activity of the and desaturases between a non-essential fatty acid (e.g. oleic acid) and an essential fatty acid (see above). If the latter is deficient, oleic acid is readily converted, via the desaturases, to Mead acid, since there is little competition (Figure 11.14). Hence the amount of the latter can be used as a marker for deficiency of essential fatty acids, although it is better to use the ratio of double bonds only three are present in Mead acid (i.e. a triene) but four are present in arachidonic acid (i.e. a tetraene). A ratio in plasma, triene/tetraene >4.0 is an indication of a deficiency of essential fatty acids. This method has shown that a deficiency can occur in a number of conditions which can lead to disease (Table 11.5). 

It is claimed that chronic deficiency of arachidonic acid can lead to a number of medical problems that can be overcome by supplementation of a normal diet with evening primrose oil. Supplementation is claimed to lead to an alleviation of eczema reduction in premenstrual tension and breast pain during menstruation improvement in some chronic inflammatory and autoimmune diseases reduction in blood pressure in hypertensive patients and reduction in blood cholesterol levels. As might be expected, these claims are controversial, but they serve to illustrate how basic biochemical information can lead to a considerable lay interest in a subject. 

Figure 11.17 Supplementation of diet with y-linolenic acid to overcome a deficiency of A desaturase Supplementation of a diet with DOPA to overcome a deficiency of monooxygenase in Parkinson s disease. A desaturase is a rate-limiting enzyme in the synthesis of arachidonic acid. Supplementation of diet with y-linolenic acid bypasses this enzyme. Damage to neurones in the brain that use dopamine as a neurotransmitter causes a deficiency of rate-limiting a supplement - enzyme, tyrosine monooxygenase, which is bypassed by a supplement, DOPA (dihydroxyphenylalanine). DOPA (usually, described as L-DOPA) is considered by the medical profession as a drug but, in reality, it is a dietary supplement.

Two fatty acids are dietary essentials in humans (see p. 361) linoleic acid, which is the precursor of arachidonic acid, the sub strate for prostaglandin synthesis (see p. 211), and linolenic acid, the precursor of other co-3 fatty acids important for growth and development. [Note A deficiency of linolenic acid results in decreased vision and altered learning behaviors.] Arachidonic add becomes essential if linoleic acid is deficient in the diet. 

The conversion of oleoyl-CoA to linoleoyl-CoA is accomplished by some insects118 but does not take place in most animals. As a result of this biosynthetic deficiency, polyunsaturated fatty acids such as linoleic, linolenic, and the C20 arachidonic acid are necessary in the diet (Box 21-B). One essential function of linoleic acid is to serve as a precursor of prostaglandins and related prostanoids (Section D). Dietary linoleate is converted to its Co A derivative and then by sequential A6 desaturation,119 elongation, and then A5 desaturation, to the 20 4 (A5 8 11 14) arachidonoyl-CoA (Fig. 21-2, lower right). These acids are referred to as 0)6 because of the position of the last double bond. Linolenic acid can be converted in an analogous fashion to the CoA derivative of the 20 5 (A5 8 11 14 17 co6) eicosapentaenoic acid (EPA). The 22 6 docasahexaenoic acid (DHA Fig. 21-2) is apparently formed by elongation of the 22 5 acyl-CoA to 24 5, desaturation, transfer to a peroxisome or mitochondrion, and p oxidation to shorten the chain.953... 

Further evidence for the involvement of vitamin E in arachidonic acid metabolism comes from work by Valentovic, Gairola and Lubawy [146], who showed that vitamin E deficiency in rats increased hepatic lipid peroxidation and decreased aortic PGI2 synthesis. Inhalation of cigarette smoke by the rats increased platelet TXA2 by over 90% and reduced aortic PGI2 by between 26-33%. However, these effects were independent of the presence of vitamin E in the diet. 

COX-2 are mainly involved in PGI2 formation and in the inflammatory process. COX-2 is inducible, for example, by pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and the control of cell growth. It promotes early atherosclerotic lesion formation in LDL receptor-deficient mice in vivo, and COX-2 is the enzyme responsible for most of the metabolism of arachidonic acid in the macrophage. 

Endothelium-dependent pulmonary artery contractions in response to arachidonic acid or methacholine appeared to be mediated by TXAj in rabbits (179). However, approximately 25% of normal New Zealand White rabbits ftuled to demonstrate pulmonary artery contraction in response to arachidonic acid, U46619 or I-BOP. These "unresponsive" rabbits were found to have only 23% of the TP receptors present on pulmonary and aortic crade membranes of "responsive" rabbits (179). Of interest was the feet that platelets fix>m "unresponsive" rabbits aggregated as well or better than platelets firom "responsive" animals vdien stirred with U46619, and no deficiency ofTP receptors nor binding affinity was found. These data sug sted that TP receptor expression may be tissue tecific. This conclusion was supported by the observation that ir bition of testosterone 5a-reductase in tats decreased TP receptor density on aortic membranes but not on platelets (180) (See V. ALTERED TP RECEPTOR FUNCTION, 3. DRUG EFFECTS, a. HORMONES below). 

Propylthiouracil, 736 Prospective study, 964 Prostaglandin F, 646 Prostaglandin II2 fPGHi), 645 Prostaglandin receptors, 646 Prostaglandins, 533, 642-643 biosynthesis, 400 classification, 645 colon cancer and, 912 conversion of arachidonic acid lo, 644-645 function, 646 Proteases, 60,63,88 action, 123-124, 444 bloixl clotting, 530-531 ca]duin>activated, 793 Protein C, 524,535 Protein deficiency, 116 Proiein density, 422 Protein efficiency ratio (PER), 469 71 Protein lunase B, 792 Protein kinase C, 786,793 Protein kinases, 54,161, IflS Protein nutrition, 458-459, 475 AIDS and. 480... 

Of adult asthmatics 2-20% have aspirin hypersensitivity (9). The mechanism is related to a deficiency in bronch-odilator prostaglandins prostaglandin inhibition may make arachidonic acid produce more leukotrienes with bronchoconstrictor activity. Oral challenge in asthmatic patients is an effective but potentially dangerous method for establishing the presence of aspirin hypersensitivity (63). 

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