Shark Liver Oil

Scientific Name(s):Shark liver oil (SLO) may be obtained from several species of sharks, including the deep sea shark ( Centrophorus squamosus ), the dogfish shark ( Squalus acanthias ), and the basking shark ( Cetorhinus maximus ).

Uses

Shark liver oil (SLO) has been used to help treat cancer, skin conditions, and respiratory ailments, as well as to reduce recurrent aphthous stomatitis and prevent radiation sickness. However, limited clinical data are available. Alkylglycerols have been studied as an immune system stimulant. Animal data suggest SLO may improve fertility.

Dosing

SLO marketed under the name isolutrol has been studied in a clinical trial of acne at a topical concentration of 0.15 g per 100 mL.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Few toxic effects have been reported. SLO supplements may have an unpleasant taste and/or odor. There have been reports of SLO-induced pneumonia in humans and pigs.

Toxicology

No adverse reactions or effects on mortality were noted in rats receiving short- and long-term doses of a supercritical fluid extract of SLO at doses 100 to 200 times that of normal human consumption. In Sweden, a SLO product ( Ecomer ) was prohibited for use by the National Board of Health and Welfare because of suspected adverse effects.

SLO is commercially produced from the livers of several species of deep sea sharks. SLO is a major natural source of squalene and alkyglycerols. 1

History

In 1916, squalene was isolated from SLO. 2 Initially, SLO was employed by Scandinavian fishermen to treat skin conditions, respiratory ailments, and certain cancers. The oil has been historically used to treat what was referred to as glandular disease that today most likely would be lymphadenopathy. 3 The active components, alkylglycerols, have been studied in a number of areas, including use as an immune system stimulant. 4

Chemistry

SLO contains alkylglycerols, squalene, pristane, vitamins A and D, esters of fatty acids, glycerol ethers, triglycerides, cholesterol, and fatty acids. 1 The composition of SLO differs among shark species and depends on the size of the shark (the liver constitutes about 25% of the total shark body weight), 1 diet, gender, growth rate, swimming depth, and reproduction. 5 Alkylglycerols are a group of ether-linked glycerols found in a number of shark species. For example, 1-O-(2-hydroxyalkyl) glycerols, 1-O-(2-methoxyhexadecyl)-glycerol, 1-O-(2-methoxy-4-hexadecenyl)-glycerol, and 1-O-(2-methoxy-4-octadecenyl)-glycerol have been isolated from Greenland SLO. 6 , 7 Dogfish shark liver contains 40% to 70% SLO, of which 30% to 40% are 1-O-alkyl diacylglycerol ethers. 8 Purification and characterization of deep sea SLO 1-O-alkylglycerols have been performed. The oil contained glycerol esters and 60% unsaponifiable matter, including squalene (45%) and cholesterol (4.5%). 9 Between 60% to 90% of liver weight in Centrophorus species is squalene-rich oil, which increases in concentration with the age of the shark. More than 50 fatty acids have also been identified. 10

Squalene is a triterpene compound that received its name because it was first isolated from shark liver oil ( Squalus spp.). SLO is considered to be the richest source of squalene. 11 Analyses of shark liver components from the late 1960s through the early 1970s include the following: oil composition of the basking shark, including sterols and glyceryl esters; 12 , 13 separation of neutral lipids from shark liver; 14 and hydrocarbon and fatty acid research. 15 , 16

Uses and Pharmacology

Cancer

An early use of alkylglycerols from SLO was to help treat leukemia and prevent radiation sickness from cancer x-ray therapy. 4 Another report suggested that alkylglycerol radioprotective effects may operate by a mechanism by which they are incorporated into a pool of platelet-activating factors, resulting in increased biosynthesis. 17 Another effect of alkylglycerols includes the ability to stimulate the immune system. One mechanism may include activation of macrophages. 4 The antitumor effects of SLO may be attributed to inducing apoptosis in neoplastic cells, suppressing signal transduction, blocking angiogenesis, promoting transmembrane transport of cytotoxic substances, and shifting the profile of cytokines. 18 Polyunsaturated fatty acids n-3 and n-6 found in SLO have been suggested to have anticarcinogenic effects. Specifically, carcinogenesis appears to be affected by the n3:n6 ratio, with a higher ratio (eg, increasing the amount of n-3) conferring greater anticarcinogenic effects. 5

Animal data

The natural alkylglycerol level rises within tumor cells as an attempt to control cell growth. An essential step in cell proliferation involves activating protein kinase C, which can be inhibited by alkylglycerols. SLO demonstrated inhibitory actions against cutaneous angiogenesis in certain cancer cells in mice. 19

The efficacy of alkylglycerols on skin papillomas was assessed in 8-week-old BALB/c mice. Twenty-four weeks after initiation, the application of alkylglycerols from SLO resulted in a 4-fold decrease in the number of papillomas. The period of latency was extended from 7 to 10 weeks. The authors concluded that alkylglycerols may exert an antipromoting effect. 20

Another study in mice assessed the efficacy of SLO compared with purified natural 1-O-alkyl- sn -glycerols (alkyl-Gro) on solid tumor growth, metastasis, and angiogenesis. Tumor growth inhibition of the 3LL-grafted carcinoma was similar between the mice treated with SLO (−29 ± 3% compared with control) and alkyl-Gro (−26% ± 3%) with a slight delay in inhibition with alkyl-Gro compared with SLO. Additionally, SLO appeared to decrease pulmonary metastasis by 31 ± 8% below control, and alkyl-Gro reduced this rate by 64 ± 8%. Finally, 5 days of treatment with alkyl-Gro was associated with a 26 ± 9% reduction in the tumor blood vessel endothelial marker compared with the control group. The authors concluded that alkyl-Gro and SLO seemed to exhibit antitumor and antiangiogenesis effects. The slightly faster effect of SLO at reducing tumor growth may be attributed to the fatty acids found in SLO. 21

An in vivo model of Lewis lung carcinoma cells in mice assessed the activity of each compound in alkyl-Gro. The authors discovered that 1-O-( Z )-9-Hexadecenyl- sn -glycerol and 1-O-( Z )-9-Octadecenyl- sn -glycerol were associated with the highest antitumor activity and were most potent on lung metastases. Saturated alkyl-Gro had weaker or no activity. In fact, one of the alkylglycerols investigated (1-O-Octadecyl- sn -glycerol) appeared to increase tumor growth and metastasis. 22

In a study of mice injected with sheep red blood cells, SLO augmented delayed-type hypersensitivity responses after 48 hours, with 20 and 50 mg/kg/day having the maximum effects on these responses. An intraperitoneal injection of SLO given to mice with breast cancer tumors increased the percentage of CD8+ lymphocytes compared with the nontreated group ( P < 0.026). Tumor growth was also reduced with SLO 10 mg/kg/day, but it was not statistically significant when compared with the mice receiving an injection of Tyrode buffer. SLO was also associated with an increase in interferon-gamma production. 18

Clinical data

A Danish study reported fewer cases of irradiation damage in alkoxyglycerol-treated uterine cancer patients. Alkoxyglycerol also may increase leukocyte and thrombocyte counts at specific dosages. However, a conflicting report finds no inhibition of tumor growth in alkoxyglycerol-treated cancer patients, even though it was used in Denmark as a supplementary agent in cancer treatment. 23

SLO had apparent inhibitory actions in human kidney cancer, and human urinary bladder cancer cells, as well as sarcoma L-1. 24

The effects of a commercialized formulation of SLO ( Ecomer ) on 5 human cell lines (eg, ovarian carcinoma, mammary carcinoma, 3 prostate cancer cell lines) were assessed in a colony-forming assay. Overall, the ovarian cell line was the least sensitive to Ecomer SLO, and the mammary carcinoma line demonstrated moderate sensitivity. All 3 of the prostate cancer cell lines were highly sensitive to SLO, with a reduction in the colony number occurring at small doses. Ovarian and prostate cancer cell lines showed an increase in the percentage of apoptotic cells compared with the mostly necrotic cells in the mammary carcinoma line noted after exposure to Ecomer . 3

Immunology
Animal data

SLO at doses of 32 g/day were provided to pregnant and eventually lactating sows. They were vaccinated against Aujeszky disease prior to term. Sows receiving SLO had higher erythrocyte and hemoglobin levels compared with controls as well as higher immunoglobulin G (IgG), alkylglyerol, and n-3 polyunsaturated fatty acids concentrations in mammary secretions. Leukocyte and IgG concentrations were also higher in the piglets born to supplemented sows. An increase in Aujeszky antibodies was noted in the blood and colostrum of sows receiving SLO as well as an increase in antibody levels in the piglets. These results suggest SLO may improve active and passive immunity in the offspring of supplemented sows. 25

Exercise is well-known to induce changes in the immune system. A study in rats was conducted to assess the effects of exercise and SLO supplementation on various immune responses. Phagocytosis, lysosomal volume, superoxide anion, and hydrogen peroxide production by peritoneal macrophages and blood neutrophils were not impacted by SLO supplementation. However, spleen and thymus lymphocyte proliferation were higher in the rats that were given SLO and/or exercise compared with those who did not receive SLO and/or exercise. Even though SLO and exercise positively impacted lymphocyte proliferation, the association did not cause further stimulation in adaptive immunity nor to impact innate immunity. 26

Clinical data

One study in patients with active rheumatoid arthritis found that SLO supplementation was able to normalize complement levels, natural killer cell activity, and reaction oxygen intermediates by peripheral blood leukocytes. 27

Additionally, squalene has been used as an immunologic adjuvant in vaccines such as malaria, human immunodeficiency virus, herpes virus, cytomegalovirus, human papillomavirus, and seasonal flu. Vaccines against influenza A (H1N1) in 2009 contained squalene in Europe. 28

Recurrent aphthous stomatitis
Animal data

Research reveals no animal data regarding the use of shark liver oil for recurrent aphthous stomatitis (RAS).

Clinical data

Twenty-five patients with RAS received SLO for 3 months. After treatment, the frequency of occurrence of RAS was 0.95 compared with 1.56 at baseline. Additionally, there was a reduction in the number of lesions per month during the third month of treatment. This effect was noted 2 months after receiving treatment. SLO also exerted immunomodulatory activity (eg, increase in the percentage of T cells, normalization of B cell and T CD3/HLA DR+ cell percentages, and decrease in the level of C4 and hemolytic activity of the complement system). 29

Cardiovascular effects

Squalene is an intermediate in the synthesis of cholesterol and bypasses HMG-CoA reductase in this pathway. 30 Therefore, it has been studied for its effects on atherosclerosis and cardiovascular disease.

Animal data

Squalene effects on cholesterol were assessed in hamsters given diets with 0.05%, 0.1%, or 0.5% squalene or 0.05% squalene-containing SLO for 4 weeks. Total cholesterol concentrations increased by 32% in the 0.05% squalene group, 23% in the 0.1% squalene group, 35% in the 0.5% squalene group, and 19% in the SLO group when compared with the control group. Statistical significance ( P < 0.05) was reached in the 0.05% and 0.5% squalene groups only. A similar effect on triglycerides was also noted. High-density lipoprotein levels increased in the 0.1% squalene, 0.5% squalene, and 0.05% SLO groups compared with the control group. The authors concluded that squalene and SLO are hypercholesterolemic, and exert caution when recommending products with these ingredients to consumers. 30

An in vitro study assessed the effect of alkyl-Gro on rabbit platelet function. Alkylglycerols had no impact on the spontaneous release of serotonin. However, alkyl-Gro partially inhibited platelet-activating factor–induced serotonin release. 31

Clinical data

Limited data are available regarding the use of SLO on cardiovascular parameters in humans. One Russian study indicated improvements in clinical status, anthropometric levels, lipids, and immunology status in patients with ischemic heart disease and hypertension who consumed SLO. 32 However, cautious use is warranted until further information can be gathered regarding SLO effects on lipid parameters.

Fertility

SLO effects on fertility are not fully understood. Alkylglycerols may serve as precursors for a platelet-activating factor that has been linked in animal studies with sperm motility. 33

Animal data

The effects of SLO supplementation on sperm motility and lipid composition were assessed in 22 boars. They were divided into 2 groups (n = 11) with one group receiving SLO 40 g/day per animal and the other group receiving no supplementation. Sperm was collected on days 0, 14, and 28. Sperm motility improved by 2.9% ( P < 0.05) in boars receiving SLO supplementation compared with the control group. Velocity parameters (eg, progressive velocity, curvilinear velocity, average path velocity) improved with supplementation with effects noted between days 0 and 14 and maintained between days 14 and 28. Supplementation of SLO was also associated with increases in the proportion of n-3 and n-6 polyunsaturated fatty acids in sperm lipids that play a role in sperm maturation. The authors suggest these effects may have positive reproductive effects. 33

Another study demonstrated similar results. Incubation of boar sperm with alkyl-Gro increased their percentage motility and the velocity parameters: progressive velocity, curvilinear velocity, and average path velocity. These effects occurred 24 hours after incubation and were continued for up to 96 hours. Additionally, the percentage of pregnancies and farrows occurring by sows inseminated with sperm treated with alkyl-Gro increased by 6.35% ( P < 0.05) compared with the control group. A further increase by 11.28% occurred in the inseminated group after a longer period of time. Treatment with alkyl-Gro did not have any effects on the size of the litters. 34

Clinical data

Research reveals no clinical data regarding the use of SLO for fertility.

Other uses

SLO has been classified as a topical protectant. 1 Squalene appears to play an antioxidant role by decreasing damage caused by oxidation from free radicals to the skin. A main component of sebum, squalene's role is to protect skin surfaces from lipid peroxidation due to ultraviolet light exposure. Additionally, squalene is deeply absorbed into the skin, increasing skin flexibility and does not leave an oily residue. This has increased the attractiveness of using squalene for cosmetic purposes. 11

Patients with atopic dermatitis are prone to dry skin and disturbances in the skin, increasing their risk for bacterial and fungal infections. SLO may be beneficial for these patients by exerting antibacterial and antifungal effects. 35 Dietary SLO also has been studied for its effects on lipid and fatty acid composition in guinea pig hearts. 24 A glycerol monoether mixture from SLO was an effective skin penetration enhancer when studied in mice. 36

SLO supplementation does not appear to have a stimulating effect on milk or butter fat production despite an increase in vitamin A concentrations. 37

SLO has been investigated as a component for making capsules as part of the encapsulation process. 38

Dosage

SLO marketed under the name isolutrol has been studied in a clinical trial of acne at a topical concentration of 0.15 g per 100 mL. 39

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

It has been stated that SLO has no adverse reactions in dosages of 100 mg 3 times daily. 4 An unpleasant taste and/or odor may be noted with SLO supplementation. 38 SLO has been implicated as a causative agent of pneumonia in pigs and humans. 40 , 41 One case report describes a 76-year-old man with long-term exogenous lipoid pneumonia caused by squalene. He was asymptomatic but admitted to the hospital for further evaluation of abnormal chest x-ray findings. Though he denied respiratory symptoms, he reported symptoms consistent with gastroesophageal reflux. He had previously experienced tuberculous pleuritis in the right lung and had a long smoking history (eg, 20 cigarettes daily for 55 years). The patient reported taking 8 capsules of squalene each day (squalene 250 mg per capsule) for over a year for his health. Sometimes he would crush the capsules in his mouth before swallowing them. A chest x-ray demonstrated a consolidation in the right upper lobe, with computerized tomography findings revealing a consolidation shadow. Bronchoalveolar lavage showed lipid-laden macrophages with no microorganisms. Numerous foamy macrophages and lymphocytes in alveolar spaces and septa as well as granulomatous lesions were noted with a transbronchial lung biopsy specimen. Gas chromatography-mass spectrometry confirmed the presence of squalene in the bronchoalveolar lavage. Upon discontinuation of squalene supplementation, the consolidation shadow decreased. Thus, it is possible that crushing the capsules in the mouth along with the presence of gastroesophageal disease led to the development of exogenous lipoid pneumonia. 42

Toxicology

Pollutants such as polychlorinated biphenyls and polybrominated diphenyl ethers have been identified in raw, cold processed (eg, essentially unrefined) SLO products. 43

Animal data

A study evaluated the toxicity of acute and repeated doses of a supercritical fluid extract of SLO (AKG-1 extract) given to mice at doses 100 to 200 times greater than recommended for human consumption. No adverse effects (eg, changes in body weight, food/water consumption, histology, serum chemistry values, body weight) or effects on mortality were noted in mice receiving 2,000 mg/kg as a single oral dose. Additionally, no adverse effects or effects on mortality were noted in rats who received 1,000 mg/kg orally for 28 days. 44

Clinical data

Thirteen volunteers received squalene 3.6 g, alkylglycerols 3.6 g, and n-3 polyunsaturated fatty acids 750 mg per day for 4 weeks. Consumption of high levels of SLO exerted antimicrobial effects; however, SLO increased total cholesterol level from 182.92 ± 29.290 mg/dL at baseline to 224.46 ± 62.198 mg/dL baseline/dlf. High levels of SLO were found to exert antimicrobial effects against bacteria, viruses, and fungi. Additionally, type 1 cytokine interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 production by peripheral blood mononuclear cells was noted. 45

The Persian Gulf War syndrome, characterized by fatigue, rashes, headache, arthralgias, myalgias, lymphadenopathies, diarrhea, memory loss, autoimmune thyroid diseases, increased allergies, neurologic abnormalities, and environmental sensitivities, was believed to be linked to antibodies developed to squalene contained in vaccinations against anthrax. However, clinical data have suggested that antibodies against squalene have been detected in healthy individuals, and the presence of these antibodies is not increased by vaccines containing squalene. 28

In Sweden, a SLO product ( Ecomer ) was prohibited for use by the National Board of Health and Welfare because of suspected adverse effects. 46

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