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Toxins in Certain Indigenous Kenya Plants "TOXINS IN CERTAIN INDIGENOUS KENYA PLANTS" By SAIFUDDIN F. DOSSAJI L_____ A Thesis Submitted in Part Fulfillment for the Degree of Master of Science in the University of Nairobi 1971 This thesis has not been submitted for a degree in any other university. * aifuddin F. Dossaji -iii- CONTENTS Page A B S T R A C T ......................................... vii ACKNOWLEDGEMENTS................................ CHAPTER I ABSTRACT ......................................... 1 INTRODUCTION ..................................... 2 EXPERIMENTAL RESULTS ............................ 6 DISCUSSION....................................... 10 EXPERIMENTAL WORK ............................... 23 M a t e r i a l s ................................ 23 Paper Chromatography ................... 23 Column Chromatography ................... 24 Isolation of Macrozamin (Experimental Procedure) ............. 26 S U M M A R Y ......................................... 29 REFERENCES....................................... 31 BIBLIOGRAPHY 35 -iv- Page CHAPTER II A B S T R A C T ..............................................41 INTRODUCTION ........................................ 42 EXPERIMENTAL RESULTS AND DISCUSSION .............. 46 EXPERIMENTAL W O R K ................................... 49 E x t r a c t i o n ................................... 49 Paper Chromatography ........................ 50 Synthesis of a-amino-S-methylamino- propionic a c i d ............................ 51 CONCLUDING COMMENT .................................. 54 REFERENCES...........................................‘55 BIBLIOGRAPHY............. 57 CHAPTER III A B S T R A C T ..............................................59 INTRODUCTION ....................................... 60 EXPERIMENTAL RESULTS AND DISCUSSION .............. 66 EXPERIMENTAL W O R K ................................... 72 Plant Specimens .............................. 72 Thin-layer Chromatography ................. 72 Gas-liquid Chromatography............... 78 Extraction of Solanum incanum (Ripe and Unripe) f r u i t s ..................80 -v- Page Extraction of Other Plants............. 81 Screening for N-Nitrosamines ........ 82 Screening for Secondary Amines........ 82 CONCLUDING COMMENT ............................ 83 REF E R E N C E S ..................................... 84 BIBLIOGRAPHY 87 -vi- LIST OF ILLUSTRATIONS Figure Page 1. The Ultraviolet Absorption Spectra of A) Macrozamin and B) Cycasin........... 8 2. The Infrared Absorption Spectrum of Macrozamin.............................. 9 3. The Infrared Absorption Spectrum of Cycasin ................................ 9 4. Partial Structural Formula of Macrozamin................. 14 5. Resemblance between Macrozamin, Cycasin and N-dimethylnitrosamine ............. 19 6 . Suggested Metabolic Pathways of N- dimethylnitrosamine and the Azoxyglycosides ........................ 22 7. Flow Sheet of Macrozamin Isolation. 25 8. The Infrared Absorption Spectrum of a-amino-8-methylaminopropionic acid . 93 Table 1. Plants Screened for the Presence of N-Nitrosamines and Secondary Amines . 73 -vii- ABSTRACT During the past years, several groups of natural products have been shown to be effective poisons, whether present in plants, micro-organisms or animal tissues. Such natural poisons may represent various classes of chemical structures, including alkaloids, saponins, car­ diac glycosides, amines, polynuclear hydrocarbons, polypep­ tides, azoxyglycosides etc. On ingestion these toxins may have varied effects which may depend on the concentration level at which the toxin is ingested or on metabolic dif­ ferences among species. Consequently the compound can be acutely toxic causing death within a few hours, most of the known alkaloids, cardiac glycosides and bacterial toxins fall into this group, or it may have varied effects leading in due course to chronic illness and even death. Certain hepato-toxins and carcinogens appertain to this type. In Kenya there have been several reports on toxicity by natural products, especially among livestock, but very few toxins have been characterized. However, in special -vill- circumstances, it has been possible to identify the plant producing either severe toxicity or delayed chronic diseases in a particular locality or in groups exposed to a common environmental factor. The production of tumours of the liver, kidney and lungs following chronic feeding of crude meal prepared from the nuts of Encephalartos hildebrandtii was reported by Mugera and Nderito (1968'. E. hildebrandtii provides a source of edible starch for the natives of Kenya of the Coast Province during famine and whenever there is short­ age of food. It is also known to be eaten by livestock. The water soluble hepato-toxin, macrozamin, (methyl- azoxymethanol-8-primeveroside, CH^N = N.CH. 0. C H 0,.C 3+ 25946 o H10°5^ haS been is°lated and characterized as the lethal chenucal from the seeds of E. hildebrandtii. Macrozamin and its analogue cycasin, (methylazoxymethanol-8-glucoside ^CH3i = N ’CH20 ‘C6H11°5^ w^ich found in the Cycas species o is reported to be toxic and carcinogenic. New impetus for further research on Cycads has been the recognition of a possible relationship between the in­ gestion of cycad material and the occurrence of a severe -ix- paralytic condition. According to Mason and V7hiting in­ gestion of leaves of species of four of the genera are reported to produce a neurological disorder in cattle, involving the irreversible paralysis of the hind quarters. A new etiological approach to this neurological disorder has been suggested by Vega and Bell who isolated a non­ protein amino acid, a-amino-B-methylaminopropionic acid (CH -NH-CH -CH(NH )-COOH), from seeds of Cycas circinalis v Z fa (Cycadaceae) which they found neurotoxic in chickens during preliminary investigations. The distribution of azoxyglycosides in the Cycads suggested a fair possibility of the presence of this unusual amino-acid in the Cycads indigenous to Kenya, but it could not be detected in either E. hildebrandtii or C. thuarsii. The primary causes of most cancers are still unknown, however, the great activity and considerable diversity of carcinogenicity shown by N-nitroso-compounds have led to an increasing interest in them as possible environmental hazards. A chemical investigation of certain species of plants from the valley of "Nasampolai", Kenya, one or more of which -x- are thought to induce oesophageal and rumenal cancer in cattle, was carried out for the presence of N-nitrosamines, and secondary amines, which are implicated as possible precursors of N-nitrosamines, in an attempt to account for some epidemiological aspects of the outbreak. -xi- ACKNOWLEDGEMENTS I am deeply grateful to Professor P.A. Robins, Head of the Chemistry Department, University College Nairobi, for suggesting the research topic and for his personal interest and helpful comments. To my supervisor, Dr. G.A. Herbin, Department of Chemistry, University College Nairobi, I cannot fully acknowledge of what I owe him by way of his expert guid­ ance and encouragement. In view of the severe demands of his routine duties, his valuable assistance through many difficulties is also greatly appreciated. I am most grateful to Dr. F.G. Peers and Dr. C.A. / Linsell of the International Agency for Research on Cancer, Regional Centre, Nairobi, who brought to my attention the rumenal cancer among livestock in the "Nasampolai" valley. I should also like to thank them for providing a small grant for research purposes. My thanks to Dr. F.G. Peers, who later became one of my supervisors, for all his guidance and helpful discussions, and most of all providing the neces­ sary literature, especially those not available locally. -xii- I wish to thank Dr. G.M. Mugera of the Veterinary Faculty, University College Nairobi, for providing the nuts of Encephalartos hildebrandtii and carrying out the toxicity tests. I should like to thank Dr. Akira Kobayashi of Kagoshima University Japan, and Dr. N.V. Riggs of the Uni­ versity of New England, Australia, for their gifts of cycasin and macrozamin and helpful discussions. I also wish to thank Professor E.A. Bell of the University of Texas, Austin, U.S.A., for his kind gift of a-amino-3-methylaininopropionic acid, and helpful discus­ sions . I should also like to thank Dr. P.J. Greenway and Dr. J.B. Gillet of the East African Herbarium for their kind help in botanically identifying the plants. I also wish to express my thanks to Swakei, the Masai field worker, for collecting the plant materials for extraction purposes. Finally, I wish to thank all the individuals who have generously assisted me in the preparation of this thesis. • S.F.D. CHAPTER I ABSTRACT The water soluble hepato-toxin macrozamin, methyl- azoxymethanol-3-primeveroside ^CH3 + = N-CH2° “ CilHi9^9^ o has been isolated and characterized from the nuts of Encephalartos hildebrandtii. Macrozamin has been previously reported by other workers to be acutely toxic and carcino­ genic (2) (13) . INTRODUCTION The members of the group of plants commonly referred to as Cycads (order Cycadales) belong to an ancient family of plants which predominated over other vegetation during the greater part of the Mesozoic. They are thought to represent an intermediate evolutionary step from fern to flov/ering plant. They are palm-like plants whose stems and seeds are rich in starch, and they belong to the order Cycadales which is composed of three families and nine genera. Stems and seeds of these plants provide a source of edible starch - and are used as
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