With caveats inherent for ecologic, nutrient disappearance analyses, a healthy dietary allowance for n-3 LCFAs for current US diets was estimated at 3.5 g/d for a 2000-kcal diet. This allowance for n-3 LCFAs can likely be reduced to one-tenth of that amount by consuming fewer n-6 fats.

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Several anti-inflammatory drugs have been examined for their ability to cause a time-dependent destruction of the fatty acid oxygenase that produces prostaglandins. All of the time-dependent inhibitors contained carboxylic acid moieties, and in addition all but one of the drugs contained a halogen atom. Structural analogs (of the timedependent inhibitors) lacking halogen atoms were unable to cause a time-dependent destruction of the enzyme.The timedependent property of an inhibitor was totally eliminated after methylation of the carboxylate group. Methylation did not, however, alter the ability of the inhibitors to competitively inhibit the oxygenase.Thus, the reversible binding of the agents at the active site was not appreciably dependent upon the free carboxyl group, whereas the subsequent irreversible process was. Since the first report by Vane (1) on the inhibition of the biosynthesis Qf prostaglandins by aspirin, a wide variety of anti-inflammatory drugs has been shown to inhibit the synthesis of prostaglandins, including pyrazolones, arylacetic acids, fenamates, and salicylates (2). The concept that inflammation could be mediated by controlling prostaglandin synthesis has intensified the search for effective inhibitors of the formation of prostaglandins. Many inhibitors investigated contain hydrophobic portions likely to compete with substrate acid for binding to a hydrophobic site on the fatty acid oxygenase that produces prostaglandins. Data recently summarized (3, 4) support the concept of such a site.Time-dependent inhibition of the fatty acid oxygenase by aspirin and indomethacin was first reported in 1971 (5). Awareness of this mode of inhibition has added another dimension to our understanding of the control of prostaglandin production, since the potency of an inhibitor may not depend solely on its affinity for binding the oxygenase, but also on the amount of time the drug remains in contact with the enzyme. The mechanism of the time-dependent loss of activity is not well understood, although recent evidence suggests that aspirin may exert its time-dependent effect by acylation of the fatty acid oxygenase (6). The current results make it unlikely that acylation is a general mechanism for all time-dependent inhibitions of anti-inflammatory agents since several time-dependent inhibitors lack an activated acyl group (see Fig. 2).We initiated the present study to examine common structural features that might be associated with the time-dependent action of the irreversible agents. The enzyme (see ref. 7 for preparation) was routinely homogenized in 0.1 M Tris-HCl (pH 8.5), containing 0.67 mM phenol, to give a concentration of 20-60 mg/ml in buffer. This was allowed to stand for 30 min at 250 to increase its activity (8). MATERIALS AND METHODSDetermination of Fatty Acid Oxygenase Activity. Oxygen consumption was measured at 30 i 0.50 on a Yellow Springs Instrument Co. model 53 Oxygen Monitor. Continuous recordings were made on a dual channel recorder with one channel recording the oxygen electrod...

Considering the n-3 fatty acids to be partial agonists relative to n-6 fatty acids helps consolidate into a unified interpretation the many diverse reports and controversies on the actions of these two types of essential fatty acids. Some research reports illustrate the similarities between these two types and some emphasize the differences, leaving readers to evaluate the status of n-3 fatty acids from a viewpoint that is conceptually similar to regarding a glass of water as half empty or half full. Both n-3 and n-6 types of fatty acids must be obtained through the diet because they are not synthesized de novo by vertebrates. Both types can support important physiological and developmental processes, can form eicosanoids (prostaglandins, leukotrienes, lipoxins, etc.), can be esterified to and hydrolyzed from tissue glycerolipids, and can be metabolically elongated and desaturated to a variety of highly unsaturated fatty acids. However, some nonesterified n-6 acids are vigorously converted to potent n-6 eicosanoids that exert intense agonist actions at eicosanoid receptors, whereas the n-3 acids less vigorously form n-3 eicosanoids that often produce less intense (partial) actions. Because both types owe their presence in vertebrate tissues to dietary intake, important physiological consequences follow the inadvertent selection of different average daily dietary supplies of these two types of polyunsaturated fatty acids.