gamma linolenic acid

Summary

Summary: An omega-6 fatty acid produced in the body as the delta 6-desaturase metabolite of linoleic acid. It is converted to dihomo-gamma-linolenic acid, a biosynthetic precursor of monoenoic prostaglandins such as PGE1. (From Merck Index, 11th ed)

Top Publications

  1. Plumb J, Luo W, Kerr D. Effect of polyunsaturated fatty acids on the drug sensitivity of human tumour cell lines resistant to either cisplatin or doxorubicin. Br J Cancer. 1993;67:728-33 pubmed
    ..The combination of polyunsaturated fatty acids and cytotoxic drugs may have clinical potential provided that the normal tissue toxicities of the two treatments are not additive. ..
  2. Das U. From bench to the clinic: gamma-linolenic acid therapy of human gliomas. Prostaglandins Leukot Essent Fatty Acids. 2004;70:539-52 pubmed
    ..In view of this, large-scale, double blind studies are needed to establish the usefulness of GLA in the treatment of malignant brain tumors. ..
  3. Leaver H, Williams J, Smith C, Whittle I. Intracellular oxidation by human glioma cell populations: effect of arachidonic acid. Prostaglandins Leukot Essent Fatty Acids. 2004;70:449-53 pubmed
    Arachidonic acid (AA) and Gamma linolenic acid have been shown to limit glioma cell growth, stimulate apoptosis and lipid peroxidation...
  4. Leaver H, Wharton S, Bell H, Leaver Yap I, Whittle I. Highly unsaturated fatty acid induced tumour regression in glioma pharmacodynamics and bioavailability of gamma linolenic acid in an implantation glioma model: effects on tumour biomass, apoptosis and neuronal tissue histology. Prostaglandins Leukot Essent Fatty Acids. 2002;67:283-92 pubmed
    ..model, using the C6 glioma cell line, was used to investigate the bioactivity of locally infused n-6 HUFA gamma linolenic acid (GLA). Rat brains (15 normal and 37 C6 tumour bearing) were infused with vehicle or GLA 200 microM-2 mM...
  5. Ward G, Huang Y, Xing H, Bobik E, Wauben I, Auestad N, et al. Effects of gamma-linolenic acid and docosahexaenoic acid in formulae on brain fatty acid composition in artificially reared rats. Lipids. 1999;34:1057-63 pubmed
    ..These results suggest that dietary GLA, during development, differs from high dietary levels of AA in that it does not lead to reductions in brain DHA. ..
  6. Miyake J, Benadiba M, Colquhoun A. Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression. Lipids Health Dis. 2009;8:8 pubmed publisher
    ..Combination therapy using drugs with other, complementary targets and GLA could lead to gains in treatment efficacy in this notoriously difficult to treat tumour. ..
  7. Colquhoun A. Gamma-linolenic acid alters the composition of mitochondrial membrane subfractions, decreases outer mitochondrial membrane binding of hexokinase and alters carnitine palmitoyltransferase I properties in the Walker 256 rat tumour. Biochim Biophys Acta. 2002;1583:74-84 pubmed
  8. Leaver H, Bell H, Rizzo M, Ironside J, Gregor A, Wharton S, et al. Antitumour and pro-apoptotic actions of highly unsaturated fatty acids in glioma. Prostaglandins Leukot Essent Fatty Acids. 2002;66:19-29 pubmed
    ..The antitumour activity of three HUFA (arachidonic acid, gamma linolenic acid and eicosapentaenoic acid) were studied in glioma cells and tissue...
  9. Colquhoun A, Schumacher R. gamma-Linolenic acid and eicosapentaenoic acid induce modifications in mitochondrial metabolism, reactive oxygen species generation, lipid peroxidation and apoptosis in Walker 256 rat carcinosarcoma cells. Biochim Biophys Acta. 2001;1533:207-19 pubmed

More Information

Publications62

  1. Kenny F, Gee J, Nicholson R, Ellis I, Morris T, Watson S, et al. Effect of dietary GLA+/-tamoxifen on the growth, ER expression and fatty acid profile of ER positive human breast cancer xenografts. Int J Cancer. 2001;92:342-7 pubmed
    b>Gamma linolenic acid (GLA) possesses a number of selective anti-tumour properties including modulation of steroid receptor structure and function...
  2. Vartak S, McCaw R, Davis C, Robbins M, Spector A. Gamma-linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes. Br J Cancer. 1998;77:1612-20 pubmed
    ..The lipoxygenase inhibitor NDGA did not affect the toxicity produced by GLA. Thus, GLA is toxic to the neoplastic astrocytoma cells but not to normal astrocytes. ..
  3. Pham H, Vang K, Ziboh V. Dietary gamma-linolenate attenuates tumor growth in a rodent model of prostatic adenocarcinoma via suppression of elevated generation of PGE(2) and 5S-HETE. Prostaglandins Leukot Essent Fatty Acids. 2006;74:271-82 pubmed
    ..Taken together, the findings showed that intake of GLA-enriched diet does reduce prostatic cancer development in L-W rats and could serve as a non-toxic adjunct in management of human prostatic cancer. ..
  4. Kapoor R, Huang Y. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006;7:531-4 pubmed
    ..b>Gamma linolenic acid (GLA, all cis 6, 9, 12-Octadecatrienoic acid, C18:3, n-6), is produced in the body from linoleic acid (all ..
  5. Das U. Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies. Med Sci Monit. 2007;13:RA119-31 pubmed
    ..The low neurotoxicity of GLA to normal brain neurons and selective activity against tumor cells suggests that it could be an effective anti-glioma molecule. ..
  6. Yu Q, Shan Z, Ni K, Qian S. LC/ESR/MS study of spin trapped carbon-centred radicals formed from in vitro lipoxygenase-catalysed peroxidation of gamma-linolenic acid. Free Radic Res. 2008;42:442-55 pubmed publisher
    ..The results provided a good starting point for ongoing research in defining the possible biological effects of radicals generated from GLA peroxidation. ..
  7. Colquhoun A, Schumacher R. Modifications in mitochondrial metabolism and ultrastructure and their relationship to tumour growth inhibition by gamma-linolenic acid. Mol Cell Biochem. 2001;218:13-20 pubmed
  8. Kong X, Ge H, Hou L, Shi L, Liu Z. Induction of apoptosis in K562/ADM cells by gamma-linolenic acid involves lipid peroxidation and activation of caspase-3. Chem Biol Interact. 2006;162:140-8 pubmed
    ..The results also showed that the malondialdehyde (MDA) content was also significantly elevated, and antioxidant BHT could block GLA cytotoxity, indicating the cytotoxity induced by GLA may be due to lipid peroxidation. ..
  9. Umeda Sawada R, Fujiwara Y, Ushiyama I, Sagawa S, Morimitsu Y, Kawashima H, et al. Distribution and metabolism of dihomo-gamma-linolenic acid (DGLA, 20:3n-6) by oral supplementation in rats. Biosci Biotechnol Biochem. 2006;70:2121-30 pubmed
    ..The mechanism for GLA administration to improve atopic eczema is thought to involve an increase in the concentration of DGLA metabolized from GLA, so these results suggest that the dietary effect of DGLA would be more dominant than GLA. ..
  10. Harris N, Crook T, Dyer J, Solomon L, Bass P, Cooper A, et al. Intravesical meglumine gamma-linolenic acid in superficial bladder cancer: an efficacy study. Eur Urol. 2002;42:39-42 pubmed
    ..A response rate of 43% also indicates that MeGLA has a significant cytotoxic effect against TCC and the results are similar to those obtained using standard, single-dose, intravesical regimens. ..
  11. Leaver H, Williams J, Ironside J, Miller E, Gregor A, Su B, et al. Dynamics of reactive oxygen intermediate production in human glioma: n-6 essential fatty acid effects. Eur J Clin Invest. 1999;29:220-31 pubmed
    ..EFAs stimulated tumour cells more than normal cells (P < 0.0000017, n = 71) and increased ROIs in glial fibrillary acidic protein-positive cells in tumours. This indicated high sensitivity of glioma cell ROIs to n-6 EFAs. ..
  12. Ihara Watanabe M, Umekawa H, Takahashi T, Furuichi Y. Effects of dietary alpha- or gamma-linolenic acid on levels and fatty acid compositions of serum and hepatic lipids, and activity and mRNA abundance of 3-hydroxy-3-methylglutaryl CoA reductase in rats. Comp Biochem Physiol A Mol Integr Physiol. 1999;122:213-20 pubmed
  13. Cheng Z, Elmes M, Kirkup S, Abayasekara D, Wathes D. Alteration of prostaglandin production and agonist responsiveness by n-6 polyunsaturated fatty acids in endometrial cells from late-gestation ewes. J Endocrinol. 2004;182:249-56 pubmed
    ..The possible implications of this work are discussed in relation to the effect of diet on term and pre-term labour, which both require upregulation of the endometrial PG synthetic pathway. ..
  14. Hrastinger A, Dietz B, Bauer R, Sagraves R, Mahady G. Is there clinical evidence supporting the use of botanical dietary supplements in children?. J Pediatr. 2005;146:311-7 pubmed
  15. Furse R, Rossetti R, Zurier R. Gammalinolenic acid, an unsaturated fatty acid with anti-inflammatory properties, blocks amplification of IL-1 beta production by human monocytes. J Immunol. 2001;167:490-6 pubmed
    ..Thus, reduction of IL-1beta autoinduction may be protective in some patients with endotoxic shock and with diseases characterized by chronic inflammation. ..
  16. Seidel A, Gueck T, Fuhrmann H. The Influence of long-chain polyunsaturated fatty acids on total lipid fatty acid composition of a canine mastocytoma cell line. J Vet Med A Physiol Pathol Clin Med. 2005;52:219-24 pubmed
    ..In case the low activity of Delta5-desaturase is one of the mechanisms underlying the pathogenesis of CAD, C2 seems to be an adequate model for investigations in CAD...
  17. Senanayake S, Shahidi F. Structured lipids via lipase-catalyzed incorporation of eicosapentaenoic acid into borage (Borago officinalis L.) and evening primrose (Oenothera biennis L.) oils. J Agric Food Chem. 2002;50:477-83 pubmed
    ..2-26.8 to 37.4-39.9% (after 24 h). The highest EPA incorporations of 39.9 and 37.4% in BO and EPO, respectively, occurred at the stoichiometric mole ratio of 1:3 for oil to EPA. ..
  18. Aslan I, Ozcan F, Karaarslan T, Kıraç E, Aslan M. Decreased eicosapentaenoic acid levels in acne vulgaris reveals the presence of a proinflammatory state. Prostaglandins Other Lipid Mediat. 2017;128-129:1-7 pubmed publisher
    ..This is the first study reporting altered EPA levels and increased sPLA2 activity in acne vulgaris and supports the use of omega-3 fatty acids as adjuvant treatment for acne patients. ..
  19. Kast R. Borage oil reduction of rheumatoid arthritis activity may be mediated by increased cAMP that suppresses tumor necrosis factor-alpha. Int Immunopharmacol. 2001;1:2197-9 pubmed
    ..In this paper, evidence from published research is reviewed that indicates gamma linolenic acid component of borage oil increases prostaglandin E levels that increase cAMP levels that in turn suppress ..
  20. van Rooyen J, Swanevelder S, Morgenthal J, Spinnler Benadé A. Diet can manipulate the metabolism of EPA and GLA in erythrocyte membrane and plasma. Prostaglandins Leukot Essent Fatty Acids. 1998;59:27-38 pubmed
    ..Such a modulation could cause an accumulation of plasma TC levels that could explain the contradictory results reported by previous studies. ..
  21. Di Geronimo G, Caccese A, Caruso L, Soldati A, Passaretti U. Treatment of carpal tunnel syndrome with alpha-lipoic acid. Eur Rev Med Pharmacol Sci. 2009;13:133-9 pubmed
    ..In conclusion, the fixed association of ALA and GLA proved to be a useful tool and may be proposed for controlling symptoms and improving the evolution of CTS, especially in the earlier stages of disease. ..
  22. Mustafa G, Kursat F, Ahmet T, Alparslan G, Omer G, Sertoglu E, et al. The relationship between erythrocyte membrane fatty acid levels and cardiac autonomic function in obese children. Rev Port Cardiol. 2017;36:499-508 pubmed publisher
    ..It appears that levels of EMFAs such as linoleic acid, arachidonic acid and dihomo-gamma-linolenic acid play a role in the regulation of cardiac autonomic function in obese children. ..
  23. Hongsthong A, Subudhi S, Sirijuntarut M, Kurdrid P, Cheevadhanarak S, Tanticharoen M. Revealing the complementation of ferredoxin by cytochrome b (5) in the Spirulina- (6)-desaturation reaction by N-terminal fusion and co-expression of the fungal-cytochrome b (5) domain and Spirulina- (6)-acyl-lipid desaturase. Appl Microbiol Biotechnol. 2006;72:1192-201 pubmed
    ..Furthermore, the free form of cytochrome b (5) domain can also enhance GLA production by the Spirulina-desD gene in yeast cells. ..
  24. Kim J, Kim H, Jeong D, Kim S, Park S, Cho Y. Comparative effect of gromwell (Lithospermum erythrorhizon) extract and borage oil on reversing epidermal hyperproliferation in guinea pigs. Biosci Biotechnol Biochem. 2006;70:2086-95 pubmed
    ..Taken together, our data demonstrate that gromwell is more effective in reversing epidermal hyperproliferation with a marked increase in ceramides. ..
  25. Kamphuis M, Westerterp Plantenga M, Saris W. Fat-specific satiety in humans for fat high in linoleic acid vs fat high in oleic acid. Eur J Clin Nutr. 2001;55:499-508 pubmed
    ..Fat-specific satiety during dinner with LA vs OA was shown after a 2-week treatment of each oil, but no change in general satiety. Fat specific satiety was not related to taste perception or characterization of the oils. ..
  26. Castellanos P, Reglero M, Taggart M, Mateo R. Changes in fatty acid profiles in testis and spermatozoa of red deer exposed to metal pollution. Reprod Toxicol. 2010;29:346-52 pubmed publisher
    ..Copper levels in testis correlated positively with the percentage of 20:4n-6. The imbalance in Cu homeostasis caused by metal pollution may have caused the observed effects on deer sperm. ..
  27. Ballester M, Revilla M, Puig Oliveras A, Marchesi J, Castello A, Corominas J, et al. Analysis of the porcine APOA2 gene expression in liver, polymorphism identification and association with fatty acid composition traits. Anim Genet. 2016;47:552-9 pubmed publisher
    ..This result suggests that complex regulatory mechanisms, beyond a single polymorphism (e.g. epigenetic effects or multiple cis-acting polymorphisms), may be regulating APOA2 gene expression. ..
  28. Hrelia S, Bordoni A, Biagi P, Rossi C, Bernardi L, Horrobin D, et al. gamma-Linolenic acid supplementation can affect cancer cell proliferation via modification of fatty acid composition. Biochem Biophys Res Commun. 1996;225:441-7 pubmed
    ..In TG and CHP-212 cells, GLA was metabolized, although to a different extent, to dihomo-gamma linolenic acid and arachidonic acid. SW-620 cells neither elongated nor desaturated the incorporated GLA...
  29. Johnston G, Bilbao R, Graham Brown R. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-9 pubmed
    ..The proportion of patients who report that unsupervised dietary manipulation is beneficial has increased from 10% to 39%. ..
  30. Tahvonen R, Schwab U, Linderborg K, Mykkänen H, Kallio H. Black currant seed oil and fish oil supplements differ in their effects on fatty acid profiles of plasma lipids, and concentrations of serum total and lipoprotein lipids, plasma glucose and insulin. J Nutr Biochem. 2005;16:353-9 pubmed
    ..Serum levels of LDL cholesterol were lower (P<.05) after black currant seed oil compared to fish oil. Plasma glucose concentration decreased during the fish oil supplementation (P<.05). ..
  31. Jiang W, Redfern A, Bryce R, Mansel R. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot Essent Fatty Acids. 2000;62:119-27 pubmed
    b>Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear...
  32. Navarro Herrera D, Aranaz P, Eder Azanza L, Zabala M, Hurtado C, Romo Hualde A, et al. Dihomo-gamma-linolenic acid induces fat loss in C. elegans in an omega-3-independent manner by promoting peroxisomal fatty acid ?-oxidation. Food Funct. 2018;9:1621-1637 pubmed publisher
    ..These results point out the importance of further analysis of the activity of these omega-6 FAs, due to their potential application in obesity and related diseases. ..
  33. Yadav S, Tiwari V, Singh M, Yadav R, Roy S, Devi U, et al. Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features. J Physiol Biochem. 2017;73:187-198 pubmed publisher
    ..5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect. ..
  34. Keysser G. [Are there effective dietary recommendations for patients with rheumatoid arthritis?]. Z Rheumatol. 2001;60:17-27 pubmed
    ..In addition, patients with active RA have a slightly increased risk for cardiovascular events. Therefore, cholesterol-lowering diets and drugs should be applied early. ..
  35. Mysiakina I, Funtikova N. [Activity of NAD-dependent isocitrate dehydrogenase, isocitrate lyase, and malate dehydrogenase in Mucor circinelloides var. lusitanicus INMI under different modes of nitrogen supply]. Mikrobiologiia. 2008;77:453-9 pubmed
    ..The coupling of the cell metabolism and the lipid composition of fungal cells and the process of cell differentiation in fungi depending on the conditions of nitrogen supply is discussed. ..
  36. Ahmed S, Singh S, Pandey A, Kanjilal S, Prasad R. Application of response surface method for studying the role of dissolved oxygen and agitation speed on gamma-linolenic acid production. Appl Biochem Biotechnol. 2009;152:108-16 pubmed publisher
    To study the effect of agitation speed (rpm) and dissolved oxygen concentration (DO) on the production of gamma linolenic acid by Mucor sp. RRL001, a central composite design experiment was performed in a 5-L stirred tank bioreactor...
  37. Lindmark L, Clough P. A 5-month open study with long-chain polyunsaturated fatty acids in dyslexia. J Med Food. 2007;10:662-6 pubmed
    ..76 +/- 0.42 to 4.65 +/- 0.66 after supplementation (P < .05 by Wilcoxon sign test). Thus LC-PUFA supplementation for 5 months provides positive and clear beneficial effect on variables usually impaired by dyslexia. ..
  38. Cook D, Grierson D, Jones C, Wallace A, West G, Tucker G. Modification of fatty acid composition in tomato (Lycopersicon esculentum) by expression of a borage delta6-desaturase. Mol Biotechnol. 2002;21:123-8 pubmed
    ..These changes in fatty acid composition are thought to be beneficial for human health...
  39. Puri B. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). J Clin Pathol. 2007;60:122-4 pubmed
    ..Furthermore, both arachidonic acid and eicosapentaenoic acid are, at relatively low concentrations, directly virucidal. ..
  40. Curtis L. High-quality enteral nutrition essential for reducing morbidity and mortality in acute care patients. Crit Care Med. 2007;35:988; author reply 988 pubmed
  41. Hatanaka E, Levada Pires A, Pithon Curi T, Curi R. Systematic study on ROS production induced by oleic, linoleic, and gamma-linolenic acids in human and rat neutrophils. Free Radic Biol Med. 2006;41:1124-32 pubmed
    ..Oleic, linoleic, and gamma-linolenic acids do stimulate ROS production by neutrophils; however, measurements using the luminol-amplified chemiluminescence and cytochrome c reduction techniques require further analysis. ..
  42. Kong X, Ge H, Chen L, Liu Z, Yin Z, Li P, et al. Gamma-linolenic acid modulates the response of multidrug-resistant K562 leukemic cells to anticancer drugs. Toxicol In Vitro. 2009;23:634-9 pubmed publisher
    ..These results suggest that GLA could modulate the response to anti-cancer agents in P-gp overexpressing multidrug-resistant cells, and the mechanism may be by decreasing the P-gp expression and inhibiting P-gp function. ..
  43. Mainou Fowler T, Proctor S, Dickinson A. Gamma-linolenic acid induces apoptosis in B-chronic lymphocytic leukaemia cells in vitro. Leuk Lymphoma. 2001;40:393-403 pubmed
    b>Gamma linolenic acid (GLA) is cytotoxic to many types of human cancer cells. Most chemotherapeutic agents are cytotoxic by inducing apoptosis...
  44. Ranieri M, Sciuscio M, Cortese A, Santamato A, Di Teo L, Ianieri G, et al. The use of alpha-lipoic acid (ALA), gamma linolenic acid (GLA) and rehabilitation in the treatment of back pain: effect on health-related quality of life. Int J Immunopathol Pharmacol. 2009;22:45-50 pubmed
    ..Oral treatment with alpha-lipoic acid (ALA) and gamma-linolenic acid (GLA) for six weeks in synergy with rehabilitation therapy improved neuropathic symptoms and deficits in patients with radicular neuropathy. ..
  45. Halat K, Dennehy C. Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract. 2003;16:47-57 pubmed
    ..Patients using these products need to be informed of potential drug interactions and side effects. ..
  46. Arimura T, Kojima Yuasa A, Suzuki M, Kennedy D, Matsui Yuasa I. Caspase-independent apoptosis induced by evening primrose extract in Ehrlich ascites tumor cells. Cancer Lett. 2003;201:9-16 pubmed
  47. Ernst E. Ayurvedic medicines. Pharmacoepidemiol Drug Saf. 2002;11:455-6 pubmed
  48. Crook T, Dyer J, McCormick R, Birch B, Cooper A. The effects of meglumine gamma linolenic acid (MeGLA) on an organ culture model of superficial bladder cancer. Urol Res. 2002;30:59-65 pubmed
    ..We conclude that MeGLA is less effective in this system than on monolayer cell lines. However, it showed cytotoxic effects which were comparable to those seen with conventional agents in the same system. ..
  49. Reinikainen M, Meriluoto J, Spoof L, Harada K. The toxicities of a polyunsaturated fatty acid and a microcystin to Daphnia magna. Environ Toxicol. 2001;16:444-8 pubmed
    ..The activity equaled that of microcystin-LR, which is commonly treated as one of the most potent cyanobacterial toxins. Our results suggest that the toxic properties of PUFAs deserve more attention. ..
  50. Jiang W, Bryce R, Mansel R. Gamma linolenic acid regulates gap junction communication in endothelial cells and their interaction with tumour cells. Prostaglandins Leukot Essent Fatty Acids. 1997;56:307-16 pubmed
    ..This study examined the effect of gamma linolenic acid (GLA), an anti-cancer polyunsaturated fatty acid (PUFA), on both the gap junction communication of human ..
  51. Chen Y, Chiu W, Wu M. Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis. 2006;48:69-76 pubmed
    ..GLA-rich cream is better than placebo-based cream for alleviating uremic pruritus. It is a useful adjuvant in the management of refractory uremic pruritus. ..
  52. Lindemann J, David Pampe E, Peterkin J, Orozco Cronin P, Belofsky G, Stull D. Clinical study of the effects on asthma-related QOL and asthma management of a medical food in adult asthma patients. Curr Med Res Opin. 2009;25:2865-75 pubmed publisher
    ..An additional study of the medical food, with larger subject population and longer treatment duration, is warranted to confirm these findings. ..
  53. Ramrath S, Tritschler H, Eckel J. Stimulation of cardiac glucose transport by thioctic acid and insulin. Horm Metab Res. 1999;31:632-5 pubmed
    ..These data show that thioctic acid mimics insulin action by activating the signalling cascade at or before the level of phosphatidylinositol 3-kinase. ..