The study of lipoids with sulfur posed the problem of the relationship between their structure and biological activity. We mention this here because it not only explains the influence exerted by these agents but also because it indicates the manner in which this research has had to be developed. We have seen that, according to the systematization of the elements, sulfur represents a nonmetal anti A element, active especially at the meta zoic level. It is its action as an isolated element that appears interesting, in addition to the metabolic changes which it induces in the organism when present in a negative lipoid.

It seems that the organism generally metabolizes bivalent negative sulfur by changing it ultimately to the hexavalent form. Ferguson and du Vigneaud have studied the metabolism of methionine and cysteine which are the principal sources of sulfur in the organism. (125, 126) While the evidence we have on this subject is too limited to provide more than a working hypothesis, it would indicate that other compounds with lipidic character—the thiol containing lipids—have more important biological activity.

The metabolism of these compounds varies among individuals, especially those with abnormal conditions. The study of the excretion of sulfhy dryls through the urine, expressed as the sulfhydryl index, has served us as a guide in studying the metabolism of sulfur up to a point. The high excretion of the thiol group seems to be related not only to low oxidation but to an abnormal form, as mentioned above, since with the exaggerated excretion, the thiol level in the blood is reduced. This form is to be considered as an excremental one. This seems to be confirmed by the fact that the administration of bivalent sulfur, even in a large amount, is not followed consistently by its elimination in the form of thiols in the urine. In some subjects, an impressively high proportion of the thiols administered appears in the urine, and this is true even for relatively small doses of thiols or of bivalent sulfur as in thiosulfates. In other subjects, on the contrary, even when larger amounts are administered, the increase in elimination is minimal or does not occur at all. The abnormality in sulfur metabolism, which appears to be a limited capacity to oxidize it to the hexavalent positive form, also means an exaggerated intervention of the thiol group as such in the economy of the organism. This occurs along with symptoms and signs, previously noted, corresponding to an exaggerated oxidative intervention of fatty acids, in which processes the thiols probably take part.

We tried to study the capacity of the organism to fully oxidize thiolic sulphur by following the response to the administration of a known amount of sulfur in bivalent negative form. The change of the sulfhydryl index of urine would serve as a tolerance test for thiol metabolism.

After injections of 80 mg. of sodium thiosulfate, the differences in the capacity of various organisms to metabolize it could be seen and related to pathological conditions. This concept of thiol metabolism can be the basis for understanding an abnormal form of thiolic sulfur which may be involved in the pathogenesis of abnormal conditions. Substances containing a thiol group, such as methionine, cysteine and particularly glutathione, are present in sizable amounts in the organism, but it is not this form of thiol that intervenes in the abnormal metabolism. A large amount of the normal form of thiol is present in the blood of subjects with a low urinary sulfhydryl excretion. When another form, the abnormal one, intervenes, it is excreted in the urine. The organism eliminates this "abnormal" compound with sulfhydryls. It seems quite probable that this abnormal thiol compound is in a lipidic form since the sulfhydryl containing compound is readily extracted by ether from the urine. Its affinity for the lipidic system would explain the influence exerted upon fatty acids and the oxidative processes occurring in the lipidic system. The thiolipoids intervene catalyti cally in the oxidation of the fatty acids, as seen in experiments in vitro.

Thus, the thiol group in lipoids containing bivalent sulfur rather than metabolized sulfate would increase catabolic metabolism. Although the thiol in this abnormal form is largely eliminated by the urine, apparently as a defense mechanism against its pathological activity, some of it is probably retained in the cellular lipids where it continues its activity. Circulation of sulfur in thiolic lipidic form, with consequent impairment of its change from the bivalent negative sulfur into the hexavalent positive sulfur, would thus appear as the fundamental source of the participation of sulfur in the abnormal pattern. The influence exerted by administration of thiosulfates upon the sulfhydryl index can serve as an indication for these specific changes.

Sulfur is an anti A element and it is active as such in all the forms in which it exists in the organism, although the intensity of its action varies at different hierarchic levels. The activity of thiol as an anti A factor can be related to the influence exerted by carcinogens or other agents upon the biological activity of this radical, especially when it is taking part in the formation of enzymes. This relationship explains the results obtained by repeated injections of organ or tumor cells treated in vitro with agents having a thiol as polar group. The heterogenization induced leads to the appearance of severe changes resulting from the allergic reaction.

It is interesting to note that sulfur has an anti A tendency even in the hexavalent positive form in which it appears as sulfate. The sulfate ion has a capacity in the organism to inactivate lipoids of a positive character. The sulfate becomes bound to such substances, thereby tending also to facilitate their excretion in urine. Many of these substances are eliminated in combination with the sulfuric radical in the forms called "sulfo conjugated."

In view of this, the effect of sulfate ions appears to parallel that of the fatty acids. Both oppose substances having a positive polar character; that is, both are biologically antagonistic to anti fatty acids. In the sense that they oppose antifatty acids, both the bivalent negative and hexavalent positive sulfur have anti A activity, the first directly and the last indirectly.

The characteristic influence exerted by sulfur in its different forms is based on its action as an agent inducing changes toward increased homo tropy, by acting at levels above the cellular. This is a typical example of the relationship between an element's activity and its place in the periodic chart. Sulfur is a member of the series with homotropic action; it belongs to the period which corresponds to the metazoic compartment and thus acts above the cellular level.