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The Effect of Drugs on Physiologically Active Thiol Systems
Pages 269-294

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From page 269...
... THE EFFECT OF DRUGS ON PHYSIOLOGICALLY ACTIVE THIOL SYSTEMS Maxwell Schubert The Study Group For Rheumatic Diseases The Department of Chemistry New York University - Bellevue Medical Center New York City
From page 270...
... To cite a single specific instance, in his analysis of the action of vesicants, Bacq has not left room for the important possibilities suggested by the subsequent work of PirielOl in which is presented evidence for the action of mustard gas on collagen, a protein containing no thiols at all. TABLE 1 Drug Target of Effect Hg++ ; S406r As +++.; As++ +++ Arscnyl halides as lewisite Alkyl halides as; iodoacetate, sulfur mustards, nitrogen mustards Unsaturated carbonyls Disulfide; sulfoxide-sulfide Qui nones Nap hthoquinone s Alloxan Proximal tubule of kidney Trypanosomes, spirochetes Schistosomes, Leishmanias, Filarias Pyruvate oxidase, vesication Vesication, lacrimation, Lundsgaard effect Antibiotic Antibiotic Antibiotic, spermicide Antiplasmodic, antibiotics, clot-mechan ism p-Cells of the pancreas
From page 271...
... This is immediately followed by condensation of the positive ion formed with a remaining negative mercaptide ion because of the tendency of the latter with its electron-rich sulfur nucleus to share an electron pair with an electron-poor atomic nucleus: o © R-S- + R-S -- - R-S-S-R (H) In this way a disulfide is formed as a secondary product of the primary oxidation reaction.
From page 272...
... Among such atomic nuclei are the heavy metal ions which form very slightly dissociated mercaptides according to the type equation; 2 R-S-H + Hg+^^rtR-S-Hg-S-R + 2 H+ (VII) Trivalent arsenic and antimony, bivalent cadmium and lead, jmonovalent gold and silver readily form analogous mercaptides.
From page 273...
... Furthermore, if the driving mechanism of the reaction is the formation of slightly dissociated metal mercaptides then it could be expected that trivalent arsenic and antimony compounds might bring about similar changes. Such possibilities have never been described but would be rather easy to test.
From page 274...
... The unexpectedly high reactivity of both sulfur and nitrogen mustards is presumably related to the formation of the positive onium ions which would be expected to have a greater tendency to act as alkylating agents because of a greater tendency to yield positively charged alkyl ions than the simple alkyl halides of reaction (XIII)
From page 275...
... is also reminiscent of the similar splitting of disulfides by the same metal ions. It must also always be kept in mind that these alkyl halides can alkylate atomic nuclei other than sulfur nuclei.
From page 276...
... occurs only with more reactive carbonyl compounds such as occur in aldehydes but reactive ketonic carbonyl groups such as that of pyruvic acid also form such addition compounds which can in most cases be called semi-mercaptals. Acetylation of the hydroxyl group generally stabilizes the products.
From page 277...
... This type of condensation can also occur with great ease with other electron-rich nuclei, such as the nitrogen of amines. Amino-substituted hydroquinones have long been known to be formed by the action of many kinds of amines, even tertiary amines such as pyridine, with unsubstituted quinones.
From page 278...
... The older name of the thiol group is mercaptan, a word apparently synthesized from a Latin phrase to record the general property of the thiol compounds to capture or combine with mercury. But though this property of mercury to combine tightly with thiols has been known since the dawn of chemistry, it is only within the last few years that thought and experiment have been directed to an examination of the possibility of explaining the action of the extensively used mercurial diuretics in terms of the combination of mercury and physiologically active thiols.
From page 279...
... came to substantially the same results using mercuhydrin and further pointed out that BAL inhibition of diuresis might be due to formation of a stable, mercury-thiol complex and not to an antidiuretic action of BAL, inself. Farah and Maresh.^S thought these effects of reversing mercur ial diuresis with thiols suggested the possibility that the mechanism of action of mercurial diuretics is an inactivation of thiol enzymes responsible directly or indirectly for the resorption of salt and water from the lumen of the kidney tubules.
From page 280...
... After intravenous lethal doses of tetrathionate the kidney slices still show as strong a Prussian blue deposit as normal kidney. On the other hand estimation of the glutathione content of rabbit kidney showed a disappearance of 80 percent of the reduced glutathione after injection of a lethal dose of tetrathionate.
From page 281...
... Though this bactericidal effect of mercuric chloride is antagonized by thiols36 it cannot be reversed by thiols. 139 That mercury compounds can also inhibit enzymes supposed not to require thiols has raised suspicions as to whether in its antibacterial action mercury really attacks essential thiols.
From page 282...
... Franz41 found that one of the earliest changes, observable within a few hours after administration of tartar emetic intravenously to rabbits, was a swelling and degeneration of kidney epithelium. Harris60 found the most conspicious injury produced in rats given intravenous lethal doses of tryparsamide or stibosan was a necrosis of the convoluted tubules.
From page 283...
... Mack-worth" found them to react far more rapidly with protein thiols than with simple thiols and made the interesting observation that denatured enzymes containing no demonstrable thiol could protect active enzymes against inhibition by lacrimators. Yet under the same conditions, denatured egg albumin, known to contain active thiol, afforded no protection.
From page 284...
... 46 Such antibacterial unsaturated ketones when mixed in excess with thiols abolish the nitroprusside reaction of the thiols and when mixed with excess thiol lose their antibacterial properties. These unsaturated ketones were further found to have an inactivating effect on enzymes known to have essential thiols.
From page 285...
... Then in the central zone of dark blue color there is no glutathione and no growth, in the outer areas of faint blue color there is a certain amount of glutathione associated with normal growth and in the narrow zone between these there is no blue color at all showing a high glutathione concentration and greatly enhanced growth. These authors then show that flooding plates with formaldehyde, which is assumed to block the glutathione thiols, results in the formerly narrow colorless ring of high glutathione content now staining deep blue showing the glutathione to have been blocked.
From page 286...
... Of antimonials we can say almost the same although some antimony compounds can also react with hydroxy acids. If there is less evidence that they do react with tissue thiols this is largely because much less work has been done with antimonials.
From page 287...
... In some individual cases there is a fair amount of evidence that they do produce their effects by reaction with tissue thiols. In a few cases, notably the sulfur and nitrogen mustards, there is good evidence that at least some of their effects are unrelated to thiols.
From page 288...
... 288 BIBLIOGRAPHY 1. Anderson, H
From page 290...
... 290 56. Goffart, M
From page 291...
... 291 87. Michaelis, L
From page 292...
... 292 117. Schubert, M
From page 293...
... Handleyi/of Baylor has recently shown that mercurial diuretics do inhibit the succinic dehydrogenase enzyme which occurs in the kidney, and there is enough mercury ion in the kidney to account for the inhibition; but still, as Dr. Schubert has pointed out, it cannot be deduced that this is what actually happens.
From page 294...
... Other examples of the role of cellular distribution in the mechanism of action of sulfhydryl reactive agents may be stated. When ionic cadmium is injected into an animal, its actions on the proximal tubule of the kidney are not striking; its toxicity would suggest other sites of action which, at present, are not well understood.


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