Dietary arachidonic acid: harmful, harmless or helpful?

Mammalian cells and tissues contain substantial amounts of the n-6 PUFA arachidonic acid, especially in their membrane phospholipids. For example, platelets from human adults living on a typical Western diet have about 25% phospholipid fatty acids as arachidonic acid, while for human mononuclear cells, neutrophils, erythrocytes, skeletal muscle, cardiac tissue and liver phospholipids, arachidonic acid contents are about 22, 15, 17, 17, 9 and 20% total fatty acids, respectively. This arachidonic acid can have two origins: the diet or endogenous synthesis from a precursor, particularly linoleic acid, which is consumed in fairly high amounts in most diets. Important dietary sources of preformed arachidonic acid are eggs and meat; fish also contain arachidonic acid. Typical intakes of arachidonic acid have been estimated to be between 50 and 300mg/d for adults consuming Western-style diets. The most well-recognised functional role of cell membrane arachidonic acid is as a cell signalling molecule, either in its own right or after its conversion to oxidised derivatives known as eicosanoids. The eicosanoid family of mediators includes prostaglandins, thromboxanes, leukotrienes, lipoxins and hydroxyand hydroperoxy-eicosatetraenoic acids. To form eicosanoids, arachidonic acid is first released from cell membrane phospholipids by phospholipase enzymes. The free arachidonic acid then acts as a substrate for cyclooxygenase, lipoxygenase or cytochrome P450 enzymes, ultimately yielding the various eicosanoid metabolites. These metabolites have well-established roles in many pathological processes including thrombosis, inflammation and immunosuppression. Thus, drugs targeted at eicosanoid synthesis (aspirin, non-steroidal anti-inflammatory drugs, some steroids, cyclooxygenase2 inhibitors) and actions (leukotriene receptor antagonists) have been developed and in some cases are widely used with good efficacy. The idea has developed that, since arachidonic acid-derived mediators are involved in so many pathologies, arachidonic acid itself must be harmful. This notion is compounded by observations that free arachidonic acid is a potent platelet aggregator, induces inflammatory responses and is an immunosuppressant. Finally, the many health benefits of long chain n-3 PUFA frequently involve an ‘antagonism’ of arachidonic acid: long chain n-3 PUFA partly replace arachidonic acid in cell membranes and inhibit arachidonic acid metabolism to eicosanoids. These observations have led to the idea that both arachidonic acid and its eicosanoid derivatives are harmful. This idea is supported by a study with arachidonic acid (6 g/d as an ethyl ester) in healthy human volunteers, which was stopped early (after 3 weeks) because of a dramatic increase in ex vivo platelet aggregation, which prompted concern about a potentially adverse pro-thrombotic action of dietary arachidonic acid. An article in the current issue of the British Journal of Nutrition assesses the impact of increased dietary intake of arachidonic acid in an adult population with high fish intake. This is the first study of arachidonic acid intake in such a population; previous studies in healthy adult human subjects have been conducted in low fish consumers in the USA and in the UK. In this new study, approximately 840mg arachidonic acid/d was consumed by Japanese adults for 4 weeks. Habitual arachidonic acid intake was estimated to range between 110 and 270mg/d with an average of about 175mg/d. This is not unlike typical intakes reported for adults in Western countries. Habitual intakes of EPA and DHA ranged from 42 to 691 and from 98 to 991mg/d, respectively, with average intakes of about 310 and 550mg/d respectively. These are much greater than long chain n-3 PUFA intakes among those subjects involved in studies of arachidonic acid previously (e.g. 90 and 150mg/d for EPA and DHA, respectively). In this new study, the amount of arachidonic acid was increased in serum phospholipids (from 9·6 to 13·7 g/100 g total fatty acids) and TAG (from 1·4 to 2·3 g/ 100 g total fatty acids) with maximum incorporation occurring at 2 weeks of supplementation. The increase in arachidonic acid content of serum phospholipids is consistent with that seen in plasma phospholipids in adults in the UK supplementing their diet with 680mg arachidonic acid/d (from 9·3 to 15·9 g/100 g total fatty acids), in which maximum incorporation occurred at 4 weeks (an earlier time point was not examined). A washout period of 4 weeks resulted in a return of arachidonic acid in serum phospholipids and TAG to levels seen prior to starting supplementation. Again, this is consistent with earlier observations for plasma phospholipids after a 4-week washout period. In the study of Kusumoto et al. there was no effect of supplemental arachidonic acid on blood pressure, serum lipid and glucose concentrations or serum markers of liver function. These findings are consistent with an earlier study conducted in the USA using 1·5 g arachidonic acid/d, which showed no effects on blood lipid or lipoprotein concentrations. However, the main focus of this new study is platelet aggregation. Given this, it is unfortunate that the authors do not report the fatty acid composition of platelet phospholipids. Studies using data across populations with different patterns of PUFA intake have reported that platelet aggregation is highly related to the arachidonic acid and EPA contents of platelets. In this new study, maximal aggregation of platelets in response to ADP, collagen or arachidonic acid and platelet sensitivity to ADP or collagen were not affected by dietary arachidonic acid supplementation. Thus, the main conclusion from this new study is that increasing arachidonic acid intake by 840mg/d does not British Journal of Nutrition (2007), 98, 451–453 doi: 10.1017/S0007114507761779 q The Author 2007