Introduction
One of the beneficial effects of plant adaptogen extracts is their anti-stress effect. From this point of view evening primrose oil (EPO) may be classified as an adaptogen because some authors reported its beneficial effect in avoiding stress-induced gastro-intestinal ulcer formation [1-4]. In one of this study [3] the rats were fed EPO – enriched diet 14 days before the experiment. In the experiment, animals were subjected to the 7-hours long water- restraint stress. Diet with addition of 5% EPO decreased the creation of gastric ulcers by 50%.
Evening primrose oil is extracted from the seeds of various Oenothera species [5]. It is a source of a-6 essential fatty acids, among them, linoleic acid (LA) (59-76%) and g-linolenic acid (GLA) (8-10%). The first step of linoleic acid metabolism is d-6-desaturation to GLA. The -linolenic acid forms di-homo--linolenic acid (DGLA) further converted to prostaglandin E1 (PGE1) or to arachidonic acid metabolites (PGE2, leukotrienes, thromboxane).
Atopic eczema and diabetes represent examples of inadequate -6-desaturation.These diseases are characterized by impaired forming of active products from linoleic acid. The -linolenic acid and its metabolites are important for normal function of nerves. Disorders of nerve function occur in more than 90% of diabetics. Linoleic acid concentrations are normal or above normal in diabetic patients. However, the concentrations of its active metabolites are consistently below normal [6]. The evening primrose oil is botanical product non-affecting glucose level, that is believed to improve symptoms of neuropathy [7]. As it was experimentally demonstrated in rats, neuroactivity of EPO is mediated by cyclooxygenase and its substrates [8].
The evening primrose oil was also described as effective in atopic dermatitis and mastalgia, but optimal dosing standards and treatment regimens need clarification in adequate clinical trials [9-13].
Anti-tumor activity of evening primrose oil
Ramesh et al. [14] reported tumoricidal action of EPO, both in vitro and in vivo. This killing effect was correlated to an threefold increase in generation of free radicals in the tumor cells. The in vitro effect of n-6 fatty acids on normal and v-Ki ras transformed NIH-3T3 cells and other tumor cell lines was also described [15, 16].
It was reported, that in vivo EPO can influence carcinogen-induced papilloma formation in mice [17] and the progression of transplantable murine mammary gland adenocarcinoma [18]. Evening primrose extract induced caspase-independent apoptosis in Ehrlich ascites tumor cells, without similar effect on viability of mouse embryo fibroblast cells [19].
Up to date, no convincing evidence of EPO beneficial effects in cancer patients was presented [20, 21].
Immunotropic activity of evening primrose oil
Evening primrose oil contains aromatic compounds with radical scavenging and cyclooxygenase and neutrophil elastase inhibitory activities (3-O-trans-caffeoyl derivatives of betulinic, morolic and oleanolic acid) [22]. Antioxidant properties of evening primrose seed extracts was concentration-dependent [23].
In the in vivo study on immunomodulatory effect of dietary lipids in rats, EPO decreased the adhesion of their lymphocytes to macrophage monolayers [24]. Other authors reported that primrose oil in in vivo experiments in mice, alone or in combination with fish oil, influenced macrophage/smooth muscle cell interaction what may be beneficial for avoiding atherogenic process [25].
Peritoneal macrophages of mice fed diet containing EPO presented enhanced PGE1 synthesis [26]. Peritoneal granulocytes of rats fed for 8 weeks diet containing 15% EPO produced decreased amounts of PGE2 [27].
Diet supplemented with 20% EPO suppressed natural killer (NK) cell activity of spleen lymphocytes collected from rats [28]. Evening primrose oil-enriched diet of rats influenced their serum-cytokine levels: interferon (IFN-) and MCP-1 levels were significantly decreased, the level of tumour necrosis factor (TNF-) was stimulated [29]. In atopic dermatitis patients , however, presenting low IFN- level, EPO significantly increased the level of this cytokine [10].
Feeding weanling rats diets containing EPO (but also fish and olive oil) resulted in suppression of lymphocyte proliferation [30]. GLA and arachidonic acid (AA), and some AA metabolites induce T-regulatory cell activity and reduce pro-inflammatory cytokines production. In experimentally induced T-cell mediated autoimmune disease GLA prevent or reduce the severity [31]. However, diets with high supply of GLA precursor, linoleic acid (LA) increased significantly the production of pro-inflammatory cytokines [32].
In Sommer et al. study [33] of the effect of EPO on the in vivo angiogenic activity of blood mononuclear leukocytes (cutaneous test in mice) highly statistically significant decrease of this activity was observed when cells were collected from rheumatoid arthritis (RA) patients. No effect was seen when cells were collected from the blood of healthy donors.
Filewska et al. [34] studied the effect of EPO (OEPAROL) feeding mice and rabbits for four weeks on the number and metabolic activity (chemiluminescence test – CL) of blood granulocytes. In animals receiving higher doses of EPO (125 or 250 mg/kg in mice, 50 mg/kg in rabbits) significant lowering of granulocytes number was observed. In the same time, CL activity of these cells increased significantly. These doses corresponded (applying a coefficient of 7 for adjustment of differences between mouse and human in relation the surface to body mass) to the doses recommended by EPO producers for humans. Number and activity of granulocytes return to the pre-feeding levels 5 weeks after feeding termination. In the view of these results, it might be necessary to verify EPO doses recommended for human.
Contrary to the effects obtained in immunological angiogenesis, where topical application of EPO diminished skin neovascular reaction to the factors released by RA patients lymphocytes, EPO increased angiogenesis induced in mice skin after grafting of human lung cancer cells [35]. It was confirmed in further experiments where feeding mice linoleic acid (LA) significantly enhanced L1 Sarcoma tumor growth, vascularity and angiogenic activity [36].
In conclusion: experimental data suggest that EPO and pure linoleic acid may be harmful for cancer patients.
References
1. Al-Shabanah OA (1997): Effect of evening primrose oil on gastric ulceration and secretion induced by various ulcerogenic and necrotizing agents in rats. Food Chem Toxicol 35: 769-775.
2. Stęplewski Z, Jaskółecki H, Tyrpień M (1995): The comparative estimation of the protective activity of various specimens containing the primrose oil in the process of stress-ulcer formation. In: Olej z nasion wiesiołka w profilaktyce I terapii.Zbiór prac II Sympozjum, Łódź, 150-155.
3. Stęplewski Z, Jaskółecki H, Tyrpień M et al. (1995): The cytoprotective and regenerative activity of the primrose oil on the rat stomach mucosa during the stress reaction. In: Olej z nasion wiesiołka w profilaktyce I terapii.Zbiór prac II Sympozjum, Łódź, 156: 63.
4. Stęplewski Z, Kozak M, Miarczyńska-Jończyk H et al. (1995): The protective activity of the unsaturated fatty acids in evening primrose oil against the inhibition of the gastrointestinal stress in rats. In: Olej z nasion wiesiołka w profilaktyce I terapii.Zbiór prac II Sympozjum, Łódź, 164-167.
5. Rostański K (1995): The genus Oenothera L.(Evening primrose) in Europe. In: Olej z nasion wiesiołka w profilaktyce i terapii. Zbiór prac II Sympozjum, Łódź, 1-7.
6. Horrobin DF (1993): Fatty acid metabolism in health and disease: the role of delta-6- desaturase. Am J Clin Nutr 57 (suppl): 732S-737S.
7. Halat KM,Dennehy CE (2003): Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract 16: 47-57.
8. Julu PO, Gow JW, Jamal GA (1996): Endogenous cyclo-oxygenase substrates mediate the neuroactivity of evening primrose oil in rats. J Lipid Mediat Cell Signal 13: 115-125.
9. Szczesna M (1993): Therapeutic assessment of the evening primrose. Rocz Panstw Zakl Hig 44: 139-146.
10. Yoon S, Lee J, Lee S (2002): The therapeutic effect of EPO in atopic dermatitis patients with dry scaly skin lesions is associated with the normalization of serum gamma-interferon levels. Skin Pharmacol Appl Skin Physiol 15: 20-25.
11. Senapati S, Banerjee S, Gangopadhyay DN (2008): Evening primrose oil is effective in atopic dermatitis: a randomized placebo-controlled trial. Indian J Dermatol Venereol Leprol 74: 447-452.
12. Bayles B, Usatine R (2009): Evening primrose oil. Am Fam Physician 80: 1405-1408.
13. Pruthi S, Wahner-Roedler DL, Torkelson CJ et al. (2010): Vitamin E and evening primrose oil for management of cyclical mastalgia: a randomized pilot study. Altern Med Rev 15: 59-67.
14. Ramesh G, Das UN, Koratkar R et al. (1992): Effect of essential fatty acids on tumor cells. Nutrition 8: 343-347.
15. Cantrill RC, Ells GW, de Antueno RJ et al. (1992): The effect of n-6 fatty acids on normal and v-Ki ras transformed NIH-3T3 cells. Anticancer Res 12: 2197-2201.
16. Cantrill RC, Ells GW, DeMarco AC, Horrobin DF (1997): Mechanisms of the selective cytotoxic actions of certain essential fatty acids. Adv Exp Med Biol 400A: 539-544.
17. Ramesh G, Das UN (1998): Effect of evening primrose and fish oils on two stage skin carcinogenesis in mice. Prostaglandins Leukot Essent Fatty Acids 59: 155-161.
18. Munoz SE, Piegari M, Guzman CA, Eynard AR (1999): Differential effects of dietary Oenothera , Zizyphus mistol, and corn oils , and essential fatty acid deficiency on the progression of a murine mammary gland adenocarcinoma. Nutrition 15: 208-123.
19. Arimura T, Kojima-Yuasa A, Suzuki L et al. (2003): Caspase-independent apoptosis induced by evening primrose extract in Ehrlich ascites tumor cells. Cancer Lett 201: 9-16.
20. Boon H, Wong J (2004): Botanical medicine and cancer: a review of the safety and efficacy. Expert Opin Pharmacother 5: 2485-2501.
21. Gratus C, Wilson S, Greenfield SM et al. (2009): The use of herbal medicines by people with cancer: a qualitative study. BMC Complement Altern Med 14: 9-14.
22. Hamburger M, Riese U, Graf H et al. (2002): Constituents in evening primrose oil with radical scavenging, cyclooxygenase, and neutrophil elastase inhibitory activities. J Agric Food Chem 50: 5533-5538.
23. Birch AE, Fenner GP, Watkins R, Boyd LC (2001): Antioxidant properties of evening primrose seed extracts. J Agric Food Chem 49: 4502-4507.
24. Sanderson P, Calder PC (1998): Dietary fish oil diminishes lymphocyte adhesion to macrophage and endothelial cell monolayers. Immunology 94: 79-87.
25. Fan YY, Chapkin RS, Ramos KS (1996): Dietary lipid source alters murine macrophage/vascular smooth muscle cell interactions in vitro. J Nutr 126: 2083-2088.
26. Fan YY, Chapkin RS (1992): Mouse peritoneal macrophage prostaglandin E1 synthesis is altered by dietary gamma-linolenic acid. J Nutr 122: 1600-1606.
27. De La Puerta Vazquez R, Martinez-Dominguez E, Sanchez Perona J, Ruiz-Gutierrez V (2004): Effects of different dietary oils on inflammatory mediator generation and fatty acid composition in rat neutrophils. Metabolism 53: 59-65.
28. Yaqoob P, Newsholme EA, Calder PC (1994): Inhibition of natural killer cell activity by dietary lipids. Immunol Lett 41: 241-247.
29. Dirks J, van Aswegen CH, du Plessis DJ (1998): Cytokine levels affected by gamma-linolenic acid. Prostaglandins Leukot Essent Fatty Acids 59: 273-237.
30. Calder PC (1993): The effects of fatty acids on lymphocyte functions. Braz J Med Biol Res 26: 901-917.
31. Harbige LS (2003): Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids 38: 323-341.
32. Colin A, Reggers J, Castronovo V, Ansseau M (2003): Lipids, depression and suicide. Encephale 29: 49-58.
33. Sommer E, Skopińska-Różewska E, Pazdur J et al. (1995): The influence of topical application of OEPAROL ( evening primrose oil) on skin neovascular response induced in mice by leukocytes of rheumatoid arthritis (RA) patients. In: Olej z nasion wiesiołka w profilaktyce i terapii. Zbiór prac II Sympozjum, Łódź, 146: 9.
34. Filewska M, Skopińska-Różewska E, Sommer E (1997): Effect of evening primrose oil (EPO) on the number and chemiluminescent activity of rabbits and Balb/c mice blood granulocytes. In: Effects of xenobiotics on the immune system. Siwicki AK (ed.). IRS, Olsztyn; 147-152.
35. Sommer E, Skopińska-Różewska E, Filewska M et al. (1997): Stimulatory effect of evening primrose oil (EPO) on tumor angiogenesis. In: Effects of xenobiotics on the immune system. Siwicki AK (ed.). IRS, Olsztyn; 153-158.
36. Białas-Chromiec B, Skopińska-Różewska E, Sommer E et al. (2001): The influence of linoleic (LA) acid on the growth, vascularity and angiogenic activity of murine L-1 sarcoma. Współcz Onkol 5: 250-253.
