The study of the relationship between abnormal conditions and lipids has progressively led us to consider the existence of qualitative changes in these lipids, besides the quantitative ones. The existence of abnormal metabolic processes, and especially the fact that such abnormalities are often of long duration, could hardly be attributed to variations in the quantity of the intervening lipids alone. More probably they would result from changes in the nature of the intervening lipids themselves. We have investigated this aspect of the fatty acids present under abnormal conditions.

As a guide for the direction to be followed in these investigations, we used the information furnished by the study of rancidity. We believed rancidity would be able to indicate broadly the nature of the qualitative changes which the lipids may undergo under abnormal conditions. Conceptually, the abnormal can be considered to result from a loss of the capacity of the organism to sufficiently control occurring processes and keep them in the frame of the constants which characterize the entity. Due to this lack of effective control, the in vivo occurring changes under abnormal conditions would closely approach those which take place in vitro where such a control does not exist. These considerations led us to search for changes similar to those seen in rancidity, or occurring in vivo in lipids, under abnormal conditions.

As mentioned above, in rancidity a first group of changes concerns the polar group. Some of them result in the appearance of free fatty acids, others correspond to changes in the carboxyls themselves, while still others are represented by processes of oxidation which occur in the chain near the polar group. A second group of rancidity changes concerns the nonpolar group and especially the energetic centers present in it, the double bonds.

The study of this last group of changes led us to consider, the changes appearing in vitro under the direct influence of heat and oxygen. As part of these changes, we considered of special importance the conjugation of the double bonds seen to occur in vitro as a step in the oxidation of polyunsaturated fatty acids. This conjugation corresponds to a characteristic displacement in the molecule of two or more of the double bonds present, so as to result in parallel reciprocal positions.

While in the simple bond two tetrahedric carbons are bound through their peaks, in the double bond they are bound by one edge, and in the triple bond by a surface. In the conjugated formation, the common edges of two double bonds, being separated by one simple bond, are consequently parallel. The planes in which the electrons of these double bonds are moving for each double bond and which are perpendicular to that of the bond itself, become parallel. Through the resulting reciprocal induction their energetic value is enhanced.

We have studied systematically the different qualitative abnormalities concerning the fatty acids, guided mainly by the information obtained through the study of rancidity.

Methods Of Investigation Used

Following this line, we first investigated the forms under which the lipids in general are present in the organism. We utilized the differences in solubility between these different forms, separating them into free lipids, lipids kept in a labile bond with other constituents, as in cenapse, lipids bound through their polar group as in fats, or in the still stronger form as lipids in combinations so firm that they cannot be separated except through saponification. The method devised for this study and some examples are in Note 8A. This research showed that under abnormal conditions, very important variations occur in the amounts of the different forms. This study pointed out that the free lipids are greatly responsible for the important manifestations in which lipids appear as active agents.

In the study concerning the abnormal metabolism of the carboxyl and nearby carbons, we investigated the appearance of fatty aldehydes or ketones in blood, urine and in the cells.

One of the major problems encountered was the appearance in vivo of conjugated fatty acids, as abnormal fatty acids. In order to ascertain their presence and to measure their amounts, we had utilized three different methods of investigation: spectral analysis in ultra violet and in the first portion of the visible spectrum (Note 8B); the study of the place of the double bond in the fatty acids molecule through the fission of these molecules and the analyses of the resulting fractions. (See Note 1, Chapter 10) More recently we have tried the vapor fractionation method (gas chromatography) (Note 8C).

The first, and especially the second method, gave us valuable data permitting us to recognize the intervention of conjugated fatty acids in abnormal conditions. These studies revealed the appearance of conjugated fatty acids, especially as trienes, the increase of their amount with the progress of the conditions and especially the fact that death occurs when their concentration in the bodies has reached a critical value. This has marked the importance of these substances in physiopathology. The fact that gas chromatography did not reveal the presence of conjugated fatty acids appears due to the conditions under which the method actually works.

Later, we will frequently return to the various problems related to intervention of conjugated fatty acids. We could thus direcUy correlate the intervention of these abnormal fatty acids with the pathogenesis of the manifestations of many conditions such as trauma, shock, adrenalectomy, and especially with the noxious manifestations following irradiation. (Chapter 10)

In abnormal metabolic changes, an important factor is the intervention of abnormal fatty acids in the metabolism of chloride ions, producing an especially strong fixation of the chloride ion to the carbons at the double bonds. The conjugated double bonds in a fatty acid molecule appear to be especially suitable for this since an abnormal, irreversible fixation of chlorides occurs in two steps. First, the halogen is fixed at the extreme carbons of conjugated formations with a displacement of the double bond in the intermediary position. In the second phase, the fixation takes place in the intermediary carbons, too. (Note 8D)

Functionally, fatty acids induce activation of oxygen as a normal process, but the appearance of peroxides or irreversible fixation of chloride ions is an abnormal event.

It is the abnormal fixation of chlorides by the conjugated fatty acids which leads to a more complex group of processes involving sodium chloride metabolism. With the chloride ion fixed, the sodium ion of sodium chloride remains free to enter into other combinations, especially with a carbonate ion, producing strongly alkaline compounds. This process explains the appearance of local alkalosis as a result of the intervention of conjugated abnormal fatty acids, corresponding to the chloride phase of "D."

The division of fatty acids into four groups—1) saturated and mono unsaturated, 2) di-, tri- and possibly also tetra unsaturated, 3) tetra- and higher polyunsaturated, and 4) conjugated—corresponds schematically to the four principal roles—caloric, organizational, functional and pathogenic —which fatty acids play in the organism. These roles are seen to be dictated both by the different structures of the fatty acids and the different substances to which they are preferentially bound. The fate of a fatty acid in the organism seems to be greatly influenced by its bond to other substances. As already noted, we have called these other substances "anti fatty acids."