Urine specimens that contain abnormal oxidizing substances show significant amounts of glucuronic and sulfuric acid compounds. (Note 18)

The analysis of the conditions under which these two substances exert anti toxic activity permits a better understanding of their role in general biology. A certain parallelism exists, and has always been emphasized, between a detoxifying and an eliminating function exerted by these two radicals. Not only do sulfo- and glucurono derivatives appear in the urine, but it often has been noted that glucuronic acid intervenes when large amounts of certain substances, such as menthol and phenol, are present and there are insufficient sulfuric acid radicals to insure detoxification and elimination. When mineral sulfates are administered, the proportion of sulfo derivatives increases.

This parellelism appears especially interesting when we recognize that sulfuric acid represents the end result of the oxidation of sulfur introduced into the organism in combinations in which it is a bivalent negative element. Only a smaller amount of sulfur is introduced as a hexavalent positive element: that is, as sulfate. Sulfur is introduced mostly in bivalent negative form, as in methionine, cystine, etc. Both sulfuric and glucuronic acid result from oxidative processes, acting in one case upon the thiol group and in the other upon glucose.

The relationship between sulfuric and glucuronic acid goes still further. It has been noted that glucuronic acid appears when enough sulfuric radicals necessary for detoxifying action are not available. However, this is not entirely true since one process does not duplicate the other. Qualitative differences intervene. (Note 19)

The significance of glucuronic acid in the defense mechanism seems clearer when we recognize that, with but few exceptions such as benzoic acid, all the substances with which glucuronic acid combines are lipids or lipoids having one or more positive polar groups. The combination with glucuronic acid takes place through these positive polar groups. (Note 20)

In our view, glucuronic acid like sulfuric acid, has a specific role in the defense of the organism and this seems to be directed especially against lipids or lipoids with a positive polar group. Bound by glucuronic acids, the latter are eliminated as excremental substances. Glucuronic acid thus would act against many anti fatty acid agents. We can conceive of sulfuric and glucuronic acids as means by which organisms are protected against an exaggerated activity of anti fatty acid agents. Along the same lines, when lipoids with positive polar groups are predominant and able to act in an exaggerated manner to oppose the fatty acids physically and chemically, the same means can be utilized to reduce this exaggeration. Thus, the intervention of glucuronic acid as a result of an abnormal oxidation of glucose induced by fatty acids appears to be biologically sound. This is also true for the sulfuric radical.

The importance of these substances does not reside only in the fact that the organism can easily produce them in larger quantities than fatty acids. The fact that they combine to form excremental substances is important too, for in this way, they help in materially eliminating the anti fatty acid substances from the organism. This would not take place if only a combination with fatty acids were possible, since the esters of fatty acids are usually retained in the organism and, under certain circumstances, can again liberate their constituents. The intervention of glucuronic acid and sulfuric acid appears to be more effective than that of the fatty acids which have their own activity and are more toxic in exaggerated amounts. This appears to be especially true in the case of glucuronic acid because the amount of glucose available is practically unlimited as compared with other metabolites. Glucuronic and sulfuric acid would thus intervene in the biological antagonism between fatty acids and anti fatty acid substances, inactivating and eliminating agents from the last group, especially when in excess. Teleologically speaking, their intervention appears to be still more interesting since the body has, as part of its defense mechanism, a tendency to manufacture anti fatty acids in excess. The intervention of agents other than fatty acids would prevent a vicious circle and permit an excess of anti fatty acids to be removed by excretion.

Fatty Acids Vs. Anti Fatty Acids

This study of the relationship between fatty acids and anti fatty acids has been guided by the dualistic concept. It must be recognized, however, that the direct activity of these substances could be largely reduced to that of one group, the fatty acids. The action of anti fatty acids is largely indirect. They control and thus limit the activity of the fatty acids. It is within this framework that the different anti fatty acids selectively influence different specific functions of the free fatty acids.

The lipids and associated constituents with their multiple activities create for each entity a balance responsible for many of the manifestations of the entity. Variations in manifestations can be attributed in large part to qualitative and quantitative variations in the intervening lipids. A systematization of these variations would help us understand many of the processes encountered in normal and abnormal physiology.

As we have mentioned before, the balance between two antagonistic forces, especially for normal conditions, is not static. Instead, there is alternating predominance of the forces, which results in an oscillatory movement. Several groups of such coupled forces, each group with its proper rhythm, are at work. Operating simultaneously, they make for a series of very complicated variations. Yet analysis is possible since each of the variations follows a dualistic pattern. The variations, as they occur at different levels and with different intensities, have been identified through various tests. In a second step they have been tentatively correlated with changes in lipids. And next, didactically, lipid changes have been related to various etiologic factors, some intrinsic and some extrinsic.