Lipid peroxidation

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Lipid peroxidation is the oxidative degradation of lipids, endogenously, or in cooking. When radicals react with non-radicals, this always creates another radical. When a fatty acid reacts with a radical, a fatty acid-radical is created. This fatty acid-radical may react with oxygen to form a peroxyl-fatty acid radical. This peroxyl-fatty acid radical may react with another free fatty acid, producing two compounds: another fatty acid radical and a lipid peroxide. This cycle is ended by an anti-oxidant, or (if there are lots of radicals) by another radical, because when two radicals react, they produce a non-radical. Anti-oxidants end a radical chain reaction by getting oxidized themselves (not rendering another radical).

Lipid peroxidation yields various compounds of different stability.[1] Such carbonyls are generated by both lipid peroxidation and by autoxidation of sugars. Specific carbonyls, such as alpha-dicarbonyls, may be aldehydic or ketonic (or both) [2], and are very potent Maillard reaction intermediates, yielding advanced glycation end products (AGEs) as well as advanced lipoxidation end products (ALEs). The Maillard reaction and lipid peroxidation are intimately interrelated, and the products of each reaction influence the other, sharing intermediates and products.[3]

Susceptibility to oxidation

Polyunsaturated fatty acids are more susceptible to lipoxidation than other fatty acids because they contain multiple carbon units with double bonds. The carbon unit in between two double-bonded carbon units is called a methylene bridge. This carbon unit has less energy invested in its bonds with the two hydrogen atoms, which makes these hydrogens more reactive. Long chain saturated fatty acids (such as palmitic and stearic acid) are also subject to lipid peroxidation.[4] Oleic acid (monounsaturated fatty acid) is relatively stable.[5] Both oleic acid and palmitoleic acid act as relative lipid peroxidation inhibitors.[6]

The peroxidation index (very) roughly reflects the relative susceptibility of unsaturated fatty acids to peroxidation. In that index, monounsaturated fatty acids are considered to be 40-fold less vulnerable than fatty acids with one methylene bridge (dienoic fatty acids; containing 2 double-bonded carbon units). Trienoic fatty acids (with 3 double bonds) are twice as vulnerable as dienoic fatty acids, and tetraenoic (4 double bonds) 4-fold more vulnerable, pentaenoic (5 double bonds) 6-fold more vulnerable and hexaenoic (6 double bonds) are 8-fold more vulnerable to peroxidation than dienoic fatty acids.[7]

Endogenous lipoxidation

Enzymatic lipoxidation Whenever the membrane gets damaged / altered, due to cell proliferation, wounding or aging, and also by the extend of synaptic activity, phospholipases in the membrane are activated. These phospholipases cleave specific phospholipids localized in the phospholipid layer of the cell wal (membrane reservoirs), which liberates PUFAs. These PUFAs are broken down by lipoxygenases (LOX), which generates lipid hydroperoxides (LOOHs). Bivalent metal ions within the active site of LOX catalyse this LOOH production. LOOHs produce lipid messengers, which modulate signaling cascades, contributing to development, differentiation, function (e.g., memory) , protection, regeneration, and repair of neurons and overall regulation of neuronal, glial, and endothelial cell functional integrity. [8] The metal ions generate radicals which are transformed within the enzyme complex to non-radical molecules. "peroxyl radicals generated as intermediates cannot leave the enzyme complex" [9] "Thus radicals never leave the enzyme complex except in severe stress situations." [10] Non-radical metabolites produced through enzymatic lipoxidation may get processed by the lysosome, thus enzymatic lipoxidation contributes to autophagy. Autophagy is the recycling of cell material within the cell. Autophagy is associated to longevity.

Non-enzymatic lipoxidation If the amount of free PUFAs (the impact of the damage/change/attack) exceeds a certain amount, LOX commit suicide. (in severe stress situations)[11] Thats where the enzymatic reaction switches to a non-enzymic reaction. This suicide liberates free iron ions that react with LOOHs (nonenzymic lipid peroxidation), creating radicals.[12] These peroxylradicals (LOO*) are not liberated enzymically, and thus they are not trapped within the enzym complex. Peroxylradicals generate a second set of signalling compounds, but also cause severe damage.[13] LOOHs produced in nonenzymic reaction induce generation of ROS (reactive oxygen species) and cell death (apoptosis). Non-enzymatic lipoxidation and elevated apoptosis are involved in all inflammatory diseases and associated with the oxidation of a great variety of biological compounds, including proteins and nucleic acids.


Naturally, the lipoxidation involved in cooked is also non-enzymatic. All lipids are susceptible to oxidation, though to different degrees. Cooking oils may produce various lipid oxidation products, such as n-alkanes, branched alkanes, alkenes, n-alkanoic acids, n-alkenoic acids, carbonyls, aromatics, polycyclic aromatic hydrocarbons (PAH), and lactones. Carbonyls and fatty acids (n-alkanoic and n-alkenoic acids) make up a significant portion of the organic compounds.[14]

  • Oils and fats experience various degrees of increase in saturation during cooking/frying use, with little consistency of used cooking oil obtained from the same source.[15]
  • Unsaturated oils are more rapidly degraded. Oils with low linoleic acid and high content of palmitic acid are relatively resistant to frying temperatures.[16]
  • After thermal processing, soybean oil contained a 15-fold higher level of free fatty acids (as % of total fat; mainly triglycerides), 8-fold higher peroxide value, 39-fold higher p-anisidine value, 19-fold higher total oxidation value, 8.5-fold more reactive substances, and 2.5 fold more trans fatty acids.[17]
  • The mean trans fat content of sunflower oil used for cooking was 4.2%, compared to vegetable mixture oils 3.1%.[18]
  • Trans fatty acids levels in commercial Spanish foods differe greatly, ranging from 0.1% in refined olive oils to 20.9% in french fries.[19]
  • Olive oil is relatively resistant to frying conditions, due to superior amounts of minor antioxidant compounds, characterized by significantly reduced levels of oxidation and hydrolysis, compared to vegetable oil with higher vitamin E contents.[20] The level of these minor antioxidant compounds (phenolics) in olive oil is reduced with each time the oil is used for frying; retention of phenolics went down from 70-80% (first frying) to 20-30% (eighth frying).[21] In another study extra-virgin olive oil was clearly nongenotoxic, and flax seed oil more genotoxic than sesame seed oil, wheat germ oil and soy oil.[22] When lambs were fed 10% linseed oil (=68% PUFA) + 17% olive cake, this increased PUFA in phospholipids and vitamin E in muscle, without compromising the meat's oxidative stability.[23]
  • Fatty acid compositions of red pepper seed oils did not change with roasting time (6-12 min. at 210°C). Fatty acid profile: 74% linoleic acid, 13% palmitic acid, 10% oleic acid, 2% stearic acid, 0.4% linolenic acid, 0.3% palmitoleic acid and 0.2% myristic acid.[24]
  • After pan-frying fish, omega-6/omega-3 ratio had increased from 0.08 in raw cod to 1.01 (with olive oil) and 6.63 (with sunflower oil) in fried cod. In farmed salmon, the omega-6/omega-3 ratio hardly changed from 0.38 (raw) to 0.39 (olive oil) and 0.58 (sunflower oil) in fried salmon.[25]
  • Linseed oil added to rabbit feed enhanced long-chain polyunsaturated fatty acid biosynthesis, and increased meat oxidation after cooking of the rabbit meat.[26]
  • Supplementation of used coconut oil (20%) to the chick diet resulted in rapid accumulation of (saturated) shorter chain fatty acids (12:0 and 14:0) in liver and hepatic mitochondria, increasing cellular death rates.[27]
  • Beef contains more mono- and di-unsaturated fatty acids than poly-unsaturated fatty acids (PUFAs). Increasing PUFA in meat by increasing PUFA in feedings resulted in a 4-fold increase in lipid oxidation products due to cooking of the meat; most lipidoxidation products coming from (PUFA-initiated) auto-oxidation of the predominant mono- and di-unsaturated fatty acids.[28] In another study, cooking of beef from cattle fed a high-PUFA diet, did not result in changes in the relative distribution of fatty acids upon cooking (140°C for 30min). Cooking did not cause thermal degradation of PUFA, or thermal degradation or oxidative synthesis of conjugated linoleic acid (a trans fatty acid).[29]
  • When peanuts are roasted in a microwave, heating them shortly already significantly increases the formation of fatty acid peroxides.[30]


The body's defense against lipid peroxidation is triggered by the damage that lipid oxidation causes. Expression and activity of key enzymes involved in antioxidant and phase II detoxification pathways are elevated in response to a long term high omega-3 intake (and the resulting damage).[31] In general, water-soluble antioxidants (vitamin C, glutathione, lipoic acid, uric acid) act within the cell, and lipid-soluble antioxidants (vitamin E, carotenes, coenzyme Q) protect cell membranes from lipid peroxidation.

  • Vitamin C has both chelating and reducing properties at once. Ascorbic acid in a dose-dependent manner suppresses lipid peroxidation of reoxygenated liver tissue. [32]
  • Vitamin E protects heart phospholipids against peroxidative deterioration.[33] Vitamin E inhibits GO formation as a lipid peroxidation product[34] and substantially inhibits CML formation [35], or hardly.[36] Vitamin E levels correlate with endogenous secretory receptors in defending against plaque formation induced by AGEs.[37] Vitamin E significantly reduces malonaldehyde (lipid peroxidation product) in cooked chicken.[38]
  • Glutathione; Acetylcysteine (inhibits CML formation[39]) is derived from cysteine, and is a precursor in the formation of glutathione. The glutathione-dependent enzyme glyoxalase I metabolizes alpha-dicarbonyls.[40] There is a time-dependent effect of n-3 PUFAs on the antioxidant response systems in the heart. Not after 3 weeks, but after 14 weeks, "expression and activity of key enzymes involved in antioxidant and phase II detoxification pathways were elevated in hearts from mice fed the n-3 PUFA diet, but not in hearts from mice fed the diet containing almost no PUFA.[41]
  • Caloric restriction reduces levels of CML in collagen[42] Greater levels of pyridoxamine 5'-phosphate (a precursor of pyridoxamine) were found in liver, kidney and heart of dietary restricted animals.[43]
  • Vitamin B6 (Pyridoxal 5'-phosphate; PLP); PLP and pyridoxal are the most effective lipid glycation inhibitors.[44][45] Pyridoxamine, pyridoxine, pyridoxal and their 5'-phosphates are precursors for the active form of PLP or vitamin B6 (Pyridoxal 5'-phosphate). PLP is riboflavin-5′-phosphate dependent, derived from vitamin B2. A lack of dietary B6 increases damage by lipid peroxidation.[46] Vitamin B6 (in mg/100g) in raw foods: 0.96 (Souci et al) in sardine; 0.93 in yellowfin tuna; 0.85 in Skipjack tuna; 0.82 (Souci et al: 0.98) in wild Atlantic salmon (farmed: 0.60); 0.55 in wild Coho salmon (farmed: 0.66); 0.54 in walnuts (0.87 according to Souci et al); 0.53 in Hass avocado and beef tenderloin; 0.46 in bluefin tuna; 0.44 in King mackerel and chicken meat; 0.40 in wild Chinook salmon, Atlantic and Spanish mackerel; 0.37 in banana; 0.31 in hazelnuts; 0.30 in egg yolk; 0.29 in California avocado; 0.22 in grape juice and dutchcured herring; 0.17 in wild Sockeye salmon; 0.12 in mango; 0.10 in apple juice; 0.08 in Florida avocado; 0.05 in orange juice.[47]
  • Pyridoxamine inhibits the chemical modification of protein by ALEs during lipid peroxidation reactions.[48] Pyridoxamine chelates the metals crucial to the redox reaction.[49] Pyridoxamine traps and cleaves alpha-dicarbonyls (intermediates in glycoxidation and lipoxidation reactions).[50] It reacts with the carbonyl group in Amadori compounds and the strong stability of pyridoxamine complexes is the key in its post-Amadori inhibition action.[51] Pyridoxamine also traps reactive oxyen species (ROS)[52] In food, pyridoxamine is also present as pyridoxamine 5’-phosphate (PMP), which is converted to pyridoxamine by intestinal phosphatases. PMP (in nmol/g) in foods: 22.9 in dried small anchovy; 4.8 in chicken fillet; 4.2 in garlic; 2.6 in carrot; 1.0 in egg yolk. Pyridoxamine (in nmol/g) in foods: 2.3 in egg yolk; 2.2 in dried small anchovy, 2.0 in chicken fillet; 1.3 in carrot and 0.8 in garlic.[53] The raw meats (sashimi) of fatty seawater fishes contain a lot of PLP and/or PMP. Five portions of sushi with 20g of fatty seawater sashimi toppings would supply with vitamin B6 recommended by the Japanese RDA.[54]
  • alpha-Lipoic acid inhibits AGEs formation [55] by inhibiting lipid peroxidation.[56] alpha-Lipoic acid is endogenously derived from caprylic acid, which is endogenously synthesized and present in coconut oil (7.6%), palm kernel oil (4.8%) and sheep milk (0.12%). alpha-Lipoic acid acts with carnitine (from lysine and methionine), improving mitochondrial-supported bioenergetics and also improving general antioxidant status, attenuating any increase in oxidative stress with age.[57] alpha-Lipoic acid improves mitochondrial function [58] and reverses all three indexes of oxidative stress (protein carbonyls, lipidoxidation, oxidation-induced changes in synaptosomal membrane proteins) [59]
  • Carnitine in combination with alph-lipoic acid synergistically lower oxidative stress more than either compound alone.[60] By far the highest levels of carnitine are found in red meat.
  • Taurine (from cysteine, fish or meat) inhibits AGE formation by inhibiting lipid peroxidation[61]
  • Phenols (in plant foods) may enhance or inhibit Maillard reaction product formation. Though green tea ameliorates plasma hydroperoxide levels, it enhances CML formation. In bovine serum albumin incubated with ribose, the natural phenol desgalactotigonin inhibits, whereas quercetin and acteoside enhance CML formation.[62]
  • Curcumin is a polyphenolic bioactive compound in turmeric. In fruit-flies, curcumin at 0.05% and 0.1% of diet increased mean lifespan by 6.2% to 25.8%, decreasing malondialdehyde levels, and increasing superoxide dismutase activity.[63]
  • Oleic acid; Supplementary oleic acid protects against endogenous lipid peroxidation by reducing the production of lipid peroxidation products and reducing oxidant stress induced injury.[64] Monounsaturated fatty acids (eg oleic acid) positively correlates in cardiac muscle and life span.[65] [66] Oleic acid in foods, as percentage of total fat: Hazelnuts 77%; Olive oil 72% (2% as free oleic acid); avocado 66%; rapeseed oil and Macadamia nuts 59%; sheabutter 45%; lard 41%, sesame oil 40%; beef 39%; egg yolks and palm oil 37%; cocoa butter 33%; Brazil nuts 32%; lamb 29%; maize oil 28%; chicken 27%; butter 25%; salmon 22%; sunflower oil and turkey 21%; soybean oil 20%; herring 19%; linseed oil 18%; tuna 17%; grapeseed oil and walnut oil 16%; walnuts 15%; palm kernel oil 14%; mackerel 13%; sardine 12%; coconut oil 7%.
  • Oleanolic acid (in garlic) inhibits CML formation.[67]
  • Capsaicin (8-methyl-N-vanillyl-6-nonemide), the major pungent in hot peppers (genus Capsicum) inhibits membrane lipid peroxidation (formation of malondialdehyde) and carbonyl formation in human red blood cells.[68]
  • Ursolic acid (in apples (particularly the peel), prunes, basil, rosemary, lavender, oregano, thyme) inhibits CML formation.[69]
  • Cholesterol increases rigidity of liposome membranes, making the membrane more resistant to radical attack.[70]
  • Furan fatty acids are, after consumption, incorporated in human tissue, acting as scavengers of lipidoxidation products (LOO* and LO* radicals). Furan fatty acids are present in algae and fish.[71]

High dietary omega-3 intakes

Omega-3 fats are most susceptible to lipid peroxidation, including in the heart mitochondria. Supplemental omega-3, however, is not associated with heart attacks and/or elevated death rates. "Of 15,159 titles and abstracts assessed, 48 RCTs (36,913 participants) and 41 cohort studies were analysed. No strong evidence of reduced risk of total mortality or combined cardiovascular events. No effect of omega 3 on total mortality or cardiovascular events. [72] From another review: "Of the 3635 citations retrieved, 20 studies of 68,680 patients were included. No statistically significant association was observed with all-cause mortality, cardiac death, sudden death, myocardial infarction and stroke [url=]

The allowed intake for omega−3 is 1.6 grams/day for men and 1.1 grams/day for women. The acceptable macronutrient distribution range for omega-3 is 0.6% to 1.2% of total energy.[73] Regarding other sources, the recommendations for minimum PUFA intake to prevent gross EFA deficiency are about 3% of total energy intake. Recommendations for prevention of heart disease are 8-10% of energy. [74] In elderly Japanese subjects, a 3 gram/day increase of dietary ALA could increase serum EPA and DHA in 10 months without any major adverse effects.[75]