Mercaptans: According to the systematization of lipoids presented above, a thiol group, acting as a polar group, will form a lipoid when bound to an energetically preponderant aliphatic or cyclic nonpolar group. In the homologous mercaptan series, even the lowest members are lipoids because of the weak electrostatic forces of the thiol group.

Although methyl mercaptan is a lipoid according to our classification, this substance is too volatile to be used. Therefore, the first low member of this homologous series to be investigated was ethyl mercaptan.

The effects of ethyl mercaptan upon microbes were more limited than those seen for fatty acids. To determine the effects at the different levels of the organization, ethyl mercaptan had to be administered parenterally. As for all other members of this series, we utilized ethyl mercaptan in 5 or 10% oily solution in cottonseed oil. In acute toxicity tests, the lethal dose was found to be 145 mgs./100grams of body weight for mice, and 153 mgs./100grams for rats. The immediate effects upon nuclei were similar to, but less intense than those of conjugated fatty acid preparations leading to caryorrhexis or pycnosis in abnormal cells. No abnormal mitosis was seen in organs with high mitotic activity, such as the intestinal mucosa or bone marrow, although appreciable changes were observed in mitosis in animal tumors. A secondary effect, an exaggeration of aging processes, was first recognized, several days after administration in the changes in granulocytes at the site of injection. The average number of nuclear lobes of the leucocytes was often very high, even above seven. This was also true for leucocytes in circulating blood when the product was injected intraperitoneally or even subcutaneously in rats. The immediate effect of such injections was a prolonged leucopenia, especially a lymphopenia.

Second day wound crust pH shows a constant change toward more alkaline values

Fig. 125. Second day wound crust pH shows a constant change toward more alkaline values for all the substances having sulfur in their polar group.

The chloride content of tumors and wounds was especially increased through treatment with mercaptans. At the tissular level, local pH of the second day wound crust was increased, an effect characteristic for all lipoids with sulfhydryl as the polar group. (Fig. 125) This explains the direct effects of ethyl mercaptan upon pain and other alkaline or acid symptoms. These effects are qualitatively similar to those seen for the polyunsaturated fatty acids but much slower to appear. While placenta acid lipid preparations, for instance, produce an effect upon pain—an increase in intensity for an alkaline pattern and a decrease for an acid pattern—even within 5 to 8 minutes after parenteral administration, the effect of mercaptans is reduced and appears after half an hour, or later.

The effect upon tumors in animals was especially manifest upon a rat sarcoma originally induced by benzpyrene in our laboratories and passed through successive transplants over a period of many years. Throughout this period, this tumor showed 100% positive takes, characteristically growing to huge size, at times as large as the rest of the animal, but without ever showing either spontaneous regression or necrotic areas. When ethyl mercaptan was injected subcutaneously in daily doses of Vi cc. of a 5% solution in cottonseed oil into animals with these tumors, interesting changes were observed. If the tumors were already large, above 6 cm. in diameter for instance, only a few regressed (5/20 for tumors of 6 cm. in diameter). In tumors that did not regress, large necrotic areas developed and were followed by ulceration. Most became infected, leading to death. Tumors smaller than 6 cm. in diameter frequently regressed rapidly and then disappeared (between 9/20 and 20/20 in different experiments). No such striking results were observed in any of the other tumor strains in rats or mice treated with ethyl mercaptan, although in several, growth arrest occurred or necrotic zones appeared. Ethyl mercaptan injected in the tumors themselves induced the same necrotic changes in most animals. (Fig. 126)

The effect upon lymphatic organs was manifest. Spleen, thymus and lymph nodes were involuted in animals treated for a few days with mercaptans. The effect upon convulsions was irregular. Even with small doses, convulsions were prevented in some cases but, in general, the effect was less constant than with fatty acids. Eosinophiles decreased rapidly in animals or humans treated with this substance. All urinary analytical data were influenced by administration of mercaptan, with changes toward the patterns of type D offbalance.

Because of the very disagreeable odor of ethyl mercaptan, we were obliged to discontinue its use so that effects of this agent upon some analyses, such as surface tension, sulfhydryl and calcium excretion, could not be studied in humans.

Other Mercaptans: Superior homologues of the mercaptan series were used. They were divided into three groups. The first included propyl, butyl, amyl and hexyl mercaptans; the second, heptyl and allyl mercaptans; the third, members with more than 10 carbons. The first group produced much the same effects, which tended to diminish as the number of carbons increased. For example, effects were considerably reduced for hexyl mercaptan as compared with ethyl mercaptan. The second group—the heptyl and allyl mercaptans—produced more intensive effects. This was especially true for allyl mercaptan. Members of the third group—with longer carbon chains such as dodecyl and hexadecyl mercaptans—produced effects so slight that they seemed almost nonexistent, except upon pH of the second day wound crust, which showed values far above the range of the controls, just as with other members of this homologous series.

Influence exerted by ethyl mercaptan upon a sarcoma induced by benz pyrene

Fig. 126. Influence exerted by ethyl mercaptan upon a sarcoma induced by benz pyrene. For bigger tumors it induces constantly an ulceration, while for small tumors, their disappearance.

With the idea of using thiol as a polar group and having another center in the molecule as a secondary center, we studied a series of other substances. One was dimercapto propanol (the B A L preparation) often used for heavy metal poisoning. It proved to be completely without effect on pain, tumor growth and systemic changes. It had less activity than the higher mercaptans, which themselves were less active than polyunsaturated and abnormal fatty acids.

The difficulties encountered in administering mercaptans, mainly related to offensive odor of lower members and inactivity of the less obnoxious members, led to a search for other chemical agents that might be active without being evil smelling. Extensive study was made of various preparations that appeared to have a bivalent sulfur bond at the nonpolar group. We investigated colloidal sulfur which, if introduced in the organism, seemed to undergo changes similar to those of bivalent sulfur. We found, thus, that the sulfur absorbed after being administered in colloidal form, was almost entirely eliminated after oxidation in the form of sulfates. In animals, no pharmacodynamic influences were observed. Only the pH of the second day wound crust was increased when these preparations were administered parenterally in suspension or were given orally mixed with food, in proportions up to 4%. There was no evident change in tumor evolution in animals or humans.