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The Biochemistry of Certain Fungicides in the Animal Body

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The Biochemistry of Certain Fungicides in the Animal Body THE BIOCHEMISTRY OF CERTAIN FUNGICIDES IN THE ANIMAL BODY By THOMAS EDWARD BARMAN A Theists presented in accordance with the regulations governing the award of the degree of Doctor of Philosophy in the University of London. partment of Biochemistry, St. Mary is Hospital Medical.School, Idomdon, W.2, August, 1961. TO iii ABSTRACT OF THESIS The fates of dehydroacetic acid and of two closely related pyronee, triacetic acid lactone and imino dehydroacetic acid have been investig- ated in the rabbit and rat. The synthesis of (14Cid-dehydroacetic acid* 'from 14C.1-acetyl bromide is described; in addition, the preparation of (14031-triacetic acid lactone and [ 4O4)-imino dehydroacetic acid, both from [140 J-dehydroacetic acid, are reported. By administering these labelled compounds to rabbits and rats, it was shown that [2.40J-dehydro- acetic acid gave rise to about 10% 14002 in the expired air, (1403). triacetio acid lactone to 50% and Cihed-imino dehydroacetic acid to 2..3%. In the urines of animals dosed with PICJ-dehydroacetic acid, dehydroacetic acid itself, hydroxy-dehydroacetic acid, their respective imino derivatives, triacetic acid lactone, urea and two metabolites of. unknown structures, metabolites "X" and lin were shown to be present by colour chromatography and eutoradiography. Of these, dehydroacetic acid, its hydrozy derivative and metabolitelfiXo'have been iao1ated, and imino - dehydroacetic acid and imino'hydroxydehydroacetic acid shown to be urinary artifacts. Work done on rat liver and kidney slices has established that, while triacetic acid lactone was oxidised in both, dehydroacetic acid was only attacked to a detectable extent,in liver slices. The binding of dehydroacetic acid to plasma albumin was shown by paper electro- phoresis. 'For structural formulae, please. see fig. 1 iv pBEFACE, "We feel that the aspect of the possible longterm effect of continued ingestion of small amounts of these substances (which are undoubtedly toxic in larger amounts) upon the general health is generally overlooked". (lord Kilbracken, 1961). In recent years some 700 ohemioals have found their way into . manie food. It was, therefore, with good reason that the House of horde quite recently expressed its concern at the danger to health arising from the use of chemicals in the growing, storing and processing of food. Accordingly, the possible use of a chemical in food production should be viewed with suspicion until such a compound has been found to be without deleterioda effect on the human organism. When dehydroacetic acid was rescued from obscurity by the Doir Chemical Company and praised as having outstanding fungicidal properties, its use as a food preservative was forbidden by the U.S, Food and Drug Administration, This was thought to be necessary. because of the scanty material available on its metabolism. However, despite its ability to be absorbed AA the skin, the use of dehydroacetic acid is at present allowed in cosmetics and in certain 6 food powder preparations. In view of the above, the elucidation of v. the metaboliem of dehydroacetic acid in the animal organism would appear to be of paramount importance. The present work was carried out in the three academic years beginning October let, l958, in the Biochemistry Department of St. Mary's Hospital Medical School, The thesis is divided into five chapters. Chapter I- is a short. review of the literature pertaining to the chemistry and biological properties of dehydro- acetic acid, triacetic acid lactone and imino-dehydroacetic acid. Chapter 2 describes the synthesis of materials used, and Chapter 3 certain methods employed. Chapter I. includes the experimental results obtained during the coUrse of this work; these are discussed in Chapter 5. I am deep]; indebted to Professor R. T. Williams for his constant advice and patience in supervising this research, to Dr. D. V. Parke, without whose generous help this work would have been impossible, and to Drs. C. King, D, Robinson and J. N. Smith for much helpful advice. Special thanks are due to Mr. F. Audas and his staff or their unstinted technical assistance, and to Miss 0# M. Parkes for typing the manuscript. The Distillers Company made this research possible by the provision of the necessary funds and samples of dehydroacetic acid. CHAPTER 1. INrmaDucTiox Page Dehtdroseetie Acid ..,. 1 ?Wawa and chemical properties 1 Antimicrobial properties 6 .. Absorption and distribution 12. Toxicology 4,4o, * -Ars * op ** ors... ******** ***lie** 13 Chemical Pathology ....,....,..................,.... * .. ** edloalip 16 Detoxication Op * Ora * aaelpaeaaalkoo ** a ** afol#04,001 ****** 11 * a *** isse 17 Triacetic Acid Lactone ...... ********** p.1"......., ************ . 19 Physical and chemical properties .............-....... ***** • 19 Biological properties ,........ ****** ....,..... 21 Zaino dehydroacetic Laid iliaaroolvorerfilloOlkailbeira * iii * a * Oa ***** gait 23 CHAPTER 2. MATERIALS Syntheses of [140-Compounds * 25 Dehydroaeetic acid **** iva.aairallife00164041,1,* * eala **** 25 Triaaetio said lautone ****** 410....tesartrolosot•toloottoolos 29 'mina dehydroacetic acid faaaa.a0 **** 00.4itairodia **** **** 30 IMAM, Materials *** ** 30 - Atteepted Syntheses of Certain Pyrones ****** 31 CHAPTER 3. METHOD Metabolism %Ober 37 Estimation of Respiratory Carbon Diodde * ** 38 Chromatographic Methods * Aloreesosiorsmooss 39 Isotope Dilution Experiments ***** 0... Moat ** ** oosoorole, 39 CHAPTER 4. THE METABOLISM OP DERIDROACETIC ACID AND SOME RELATED PIRON&S IN THE RABBIT AND RAT. Chromatographic Investigations of the Urines of Animals administered certainpyronee ..,............ The Isolation of Metabolites from the Urines of two Rabbits administered Dehydroasetic Acid 51 Identification and Properties of Hydroxydehydroacetic Acid is. 53 Some Properties of Metabolite 1.I" laalitilsoolarafaifkoaaasaataikaaa 58 Page T Metabolism of [14CAJ.Dehydroacetic Acid, (1403,14riacetto Acid Eastone and i1404J-Imino debydroacetio Aoid in the intact Rabbit and Rat 58 The Conversion of Dehydroactetio Acid and Rydroxydehydroacetio acid into their respective Imino compounds in Rabbit and Rat Urines 4 ***** 44 ******** 10444•444.4 60 Tissue Slice Experiments 10,11P000 **** ** 71 The Plasma Binding of Debydroacetic Acid =AMR 5, DISCLIZION 89 APPENDIX I. Physical Properties of Certain Poems ......... 104 APPENDIX II. The Rates of Excretion of 14CO2 lathe Expired Air and total Urine Radio. activities in Rabbits and Rats sed on [140A)-Dehydroacetic Acid, ., 3Triacetio Acid Laotone or [40.4 Imino dehydroaeetio Acid 110 APPENDIX XII', Diets. 00,4104,.0,00.0041046 *** * 001004. 00040404001$ 120 REFEREWES *** 4 * 404,4 121 CHAPTER I INTRODUCTION DehYdroacetlo Acid (a) ANVARELVand Chemioal Properties Although dehydroacetic acid was discovered. as long ago as 1866 laeutber), it was not till almost a hundred years later that convincing evidence of its structure was presented (Berson, 1952). Since the turn of the century — when the compound excited the interest of several eminent chemists (Perkin, Oswald, Collie, Hilditch) — there has been a dearth of information on the chemistry of the pyrone in the literature. The first edition of Beilstein unwisely included dehydroaoetic acid in the aromatic. series, since when it is heated with barium hydroxide (Collie, 1891a; Collie and MTer.4K, 1893) orcinol is formed One might equally well argue that acetone is aromatic since it is polymerized to mesitylene on treatment with sulphuric acid! Debydroacetic acid when carefully purified by sublima— tion is a_colourless crystalline substanoe without odour or taste. It dissolves readily in acetone, benzene and hot ethanol, but is much less Soluble in carbon tetrachloride or cold alcohol. Its solubility in water is low (<100 mg./ 100 m1. at 25°) but the pyrone dissolves readily in cold aqueous alkali to give salts. The acidity dehydroacetic 2. acid (pK 5.3) is due to its enolio character; consequently it gives a blood"red colour with ferric chloride and decolourises bromine water. The 2,4Apyronone nucleus of dehydroacetio acid is reser. kably stable to hot mineral acids. Concentrated hydrochloric acid converts the compound into 2,6.0dimethy140-pyrone (Collie, 169I8) but At sulphuric acid results in deacetylation to triaoetic said lac:tone (Collie, 1891b) Whilst 83 sulphuric acid provides an isomer, namely 2,6vdimethylorone..3.- carboxylio acid. (Collie and liilditoh, 1907). Dellydroacetio acid is steam volatile but some decomposition to 2„6.dimethyl.... 4.pyrone and carbon dioxide wow% (Collie, 18910)* Dehydroaoetic acid is very susoeptible to the action of strong alkalies; acetone, mriiinn c acid, acetate and carbon dirrilde•have been mentioned as products of allsOi decamposi.. tion (Perkin, 1885 1887)• The pyrone reacts readily with he usual ketonic reagents yielding crystalline derivatives. Thus, an oxime and a phanylhydresone are known (Perkin, 1887); the latter undergoes oyalisation when treated with hydrochloric: acid (Benary 1910): Ph— Nil— N 1111 N tai G 0— 3 3 ill The act of ammonia on debydroacctio acid is rather ourious In the cold, or on gentle waraixig, an tid.2710 deriva- tive is foraged. (Ockl.lie, 1894. Refluxing with strong ammonia yields 2j6odisetbyl.4*.:pyridone..3.carbowlio acid (Collie ,and IUlditoh, 1907; Rassweiler and Adams 19214. The latter is readily de carboxylated when heated to 27CP to give 40.1utidone (Rasswsiler and Moms I9210• 4. 0 0 NH 0— OH NH3 3 cold. 0 OH 3 triacetic acid 3.aotone refliut, NH 3 2,6.dimethy1q.4..pyridone.- 3-oarboxylio
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