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the serum obtained one minute after the injection, and after two hours the test was very faint.

The conclusion is therefore justified that the gradual disappearance of the SH compound from the circulating blood is due partly to diffusion of the compound into the tissues and partly to oxidation within the blood, presumably to the corresponding disulphide (R.SSR) modification.

Do trypanosomes contain sulphydryl compounds? So far it has tacitly been assumed that Tr. equiperdum contains glutathione or at least a closely related substance or substances containing an SH group. This assumption might seem quite justified in view of the fact that Gola (1902), Buffa (1904), Heffter (1908), and Hopkins (1922) have shown that all animal and vegetable cells with an active metabolism give the nitroprusside test. It is, of course, not feasable to attempt to isolate glutathione from trypanosomes on account of the enormous amount of material which would be required for this purpose. However, it seemed desirable at least to test trypanosomes by means of nitroprusside. For this purpose dogs were injected with this organism, and after a few days, when the parasites were quite numerous in the blood, the animals were bled into sodium citrate solution. The trypanosome layer was separated from the blood corpuscles and plasma by centrifugation, washed with physiological saline, and again centrifuged. The washing was repeated several times. The final sediment of almost pure white trypanosomes, on treatment with a little solid Na,SO,, a few drops of dilute nitroprusside and concentrated ammonia gave a typical purple reaction which faded out on standing. A positive nitroprusside test was also obtained from trypanosomes grown in rats. We conclude, therefore, that there can be little doubt of the presence of a substance in Tr. equiperdum which contains a SH group.

B. DETOXIFICATION OF ARSENOXIDE BY SH COMPOUNDS AS SHOWN IN RATS.

In a previous paper (Voegtlin and Thompson, 1922) it was shown that the arsenic of arsenoxide is tenaciously retained by the body of the albino rat. During the first 24 hours following the intravenous injection of 3 c. c. M/100 arsenoxide per kilo, only 19 per cent of the arsenic injected is excreted into the intestinal tract and with the urine. This fact and the observation that the drug disappears fairly rapidly from the blood were taken as evidence that arsenoxide has a great affinity for tissues.

As in the case of trypanosomes, it seems probable that glutathione or some other SH compounds of the tissues might react with arsenoxide, and this, of course, would reduce the amount of SH compounds in the tissues to such an extent that the latter would be

injured. It was therefore of interest to determine whether an extra supply of certain SH compounds would delay the onset of the toxic manifestations produced in rats by the injection of a toxic dose of arsenoxide.

The M L D of arsenoxide is 10 c. c. M/100 per kilo, if the drug is injected intravenously. (The majority of the animals injected with this dose die.) Immediate toxic symptoms appear always during the injection of this dose of arsenoxide, as pointed out by Voegtlin and Smith (1920) and Hunt (1921). These symptoms consist of struggling, convulsive movements, lashing of the tail, rigidity of the legs, irregular respiration with long pauses, protrusion of the eyes, lacrimation, salivation, and collapse, and several minutes later dilatation of the blood vessels of the ears. The animals then temporarily recover from the state of complete collapse and die within a short time. Practically the same symptoms are produced by sodium arsenite and other arsenicals of this type (R'AsO or R'As―S).

TABLE VI.—The temporary antitoxic effect of sodium thioglycollate on the minimum lethal dose of arsenoxide” in rats.

"Arsenoxide" (10 c. c. M/100).

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The course of events is completely altered when the injection of arsenoxide is preceded by a proper dose of a SH compound. In this case, the animals tolerate the injection of arsenoxide extremely well (with exception of lacrimation and salivation), and none of the other above-mentioned characteristic symptoms appear. Detoxification of the arsenic, however, is not permanent, and the animals ultimately die after a much longer time than in the case of the controls (Tables VI and VII).

Discussion.

The observations reported in this paper clearly indicate that certain SH compounds are able to counteract the toxic effect produced by arsenoxide on trypanosomes and a representative mammal. There are no obvious reasons to doubt that similar results could be obtained on other related forms of life. In view of the fact that SH compounds appear to occur as normal protoplasmic constituents of all living cells with an active metabolism and as R. AsO compounds are highly toxic to most forms of life, it perhaps may be concluded that arsenic in this form can be regarded as a specific poison affecting the SH group of protoplasm.

It is quite likely that arsenoxide reacts chemically with the reduced form of glutathione and perhaps also with some other SH compounds which may occur in protoplasm according to the following equation:

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That similar compounds are formed with great ease in the test tube is shown by the formation of arsenic thioglycollate from As2O, and thioglycollic acid. Reactions of this type would naturally reduce the concentration of the SH compounds of the cell in proportion to the amount of arsenoxide added. If the amount of arsenic furnished to the cell should exceed a certain limit, poisoning and death would necessarily follow as a result of the reduction of the absolute amount of SH compounds below the physiological requirement.

If, on the other hand, the cell is furnished with a certain extra supply of SH compounds, interaction between arsenic and SH compounds would then not lead to a reduction of the SH compounds below the physiological requirement, and the protoplasm would escape injury.

Tanret (J. Pharm. Chim. 1909, VI series, XXX, 145) isolated from ergot ergothioneine which was shown by Barger and Ewing (J. Chem. Soc. 1911, 10, 2336) to be a histidine derivative containing an SH group.

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TABLE VII.-Illustrates the temporary antitoxic effect and the ultimate increase in the toxicity of "arsenoxide" produced by sodium thioglycollate.

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D death of one animal; S- survival at least 1 week; +++-severe "arsenoxide" symptoms; ++-marked "arsenoxide" symptoms; +slight "arsenoxide" symptoms; (-)= absence of immediate "arsenoxide" symptoms.

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