Poisoning aconite

Citrate is isomerized to isocitrate by the enzyme aconitase (aconitate hydratase) the reaction occurs in two steps dehydration to r-aconitate, some of which remains bound to the enzyme and rehydration to isocitrate. Although citrate is a symmetric molecule, aconitase reacts with citrate asymmetrically, so that the two carbon atoms that are lost in subsequent reactions of the cycle are not those that were added from acetyl-CoA. This asymmetric behavior is due to channeling— transfer of the product of citrate synthase directly onto the active site of aconitase without entering free solution. This provides integration of citric acid cycle activity and the provision of citrate in the cytosol as a source of acetyl-CoA for fatty acid synthesis. The poison fluo-roacetate is toxic because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate, which inhibits aconitase, causing citrate to accumulate. 

Greeks. The plant is known worldwide by a variety of names such as Wolfsbane, Monkshood, and Friar s Cap. The most potent variety is A. ferox or Indian Aconite, which grows only in northern India. This particulur species is so poisonous thathandlingit with the bare hands can cause serious, though probably not fatal, poisoning. 

DETAILS - The powdered root of the aconite plants have been used as a poison since the time of the ancient... 

Among the most deadly of simple compounds is sodium fluoroacetate. The LD50 (the dose lethal for 50% of animals receiving it) is only 0.2 mg/kg for rats, over tenfold less than that of the nerve poison diisopropylphosphofluoridate (Chapter 12).a b Popular, but controversial, as the rodent poison "1080," fluoroacetate is also found in the leaves of several poisonous plants in Africa, Australia, and South America. Surprisingly, difluoroacetate HCF2-COO is nontoxic and biochemical studies reveal that monofluoroacetate has no toxic effect on cells until it is converted metabolically in a "lethal synthesis" to 2R,3R-2-fluorocitrate, which is a competitive inhibitor of aconitase (aconitate hydratase, Eq. 13-17).b This fact was difficult to understand since citrate formed by the reaction of fluorooxalo-acetate and acetyl-CoA has only weak inhibitory activity toward the same enzyme. Yet, it is the fluorocitrate formed from fluorooxaloacetate that contains a fluorine atom at a site that is attacked by aconitase in the citric acid cycle. 

Toxicity. Aconitine affects both the heart and the central nervous system and is one of the most potent and quick-acting poisons. It is well absorbed from the gastro-intestinal tract and death may occur within a few minutes. The estimated minimum lethal dose is 2 mg of aconitine, 5 ml of aconite tincture (25% v/v) or 1 g of aconite root, although recovery after ingestion of 10 mg of aconitine has been reported. 

The word toxicology is derived from the Greek words toxikon (arrow poison) and toxikos (the bow). Poisons were known about and used in warfare from the earliest times. However, there were other reasons for interest in poisons, and study of them had begun by 1500 bc. The Ebers Papyrus, the earhest medical records, include references to and recipes for poisons. Many of these are recognizable, such as hemlock, the plant toxin that the Greeks used for the execution of Socrates in 399 bc. Other substances listed are aconite, which was used as an arrow poison by the Chinese, and poisonous metals such as lead and antimony. Opium, which was used for both poisonous and beneficial purposes, has been known for at least 5,000 years. 

Arsenic has long been recognized as a poison, and was reputed to have been used by Agrippina to assassinate the Roman emperor Claudius and by the Roman emperor Nero to kiU Claudius son Britannicus. In the latter case, after the first attempt had failed and had instead aroused suspicion, the arsenic was put into the water used to cool his soup rather than into the soup itself which was tested by a taster. In the seventeenth century a woman by the name of Tofana produced arsenical powders which became known as les poudres de succession , as they were used to remove obstacles like rivals, husbands, and so on. The powders contained arsenic sulphide, aconite, box, caustic lime, powdered glass, and honey. She is reputed to have committed some 600 murders. Her most well-known poison was Aqua Tofana, probably a solution containing arsenic and lead. 

COs to form oxalacetate which under anaerobic conditions is reduced to malate. The malate in turn may be converted to fumarate and succinate (Fig, 5). The last step in this series of reactions is blocked by malonate. The second pathway involves the aerobic condensation of pyruvate and oxalacetate followed by oxidation of the condensation product to form -ketoglutarate and succinate. Wood has proposed that the first condensation product of the aerobic tricarboxylic cycle is cfs-aconitic acid which is then converted to succinate by way of isocitric, oxalosuccinic, and a-ketoglutaric acids. The a-ketoglutarate is decarboxylated and oxidized to succinic acid. Isotopic a-ketoglutarate containing isotopic carbon only in the carboxyl group located a to the carbonyl would be expected to yield non-isotopic succinate after decarboxylation. This accounts for the absence of isotopic carbon in succinate isolated from malonate-poisoned liver after incubation with pyruvate and isotopic bicarbonate. 

Aconite roots can produce serious heart failure. Among the other symptoms of aconite poisoning are numbing of mouth and tongue, gastrointestinal disturbances,... 

Agarwal B, Agarwal R, and Misra D (1977) Malignant arrhythmias induced by accidental aconite poisoning. 

The activity of an enzyme may be inhibited by the presence of a toxic metabolite. Sodium fluoroacetate, known as rat poison 1080, is extremely toxic to animals. The toxic action, however, is not due to sodium fluoroacetate itself but to a metabolic conversion product, flu-orocitrate, formed through a reaction commonly known as "lethal synthesis," as shown in Figure 5.3. The resulting fluorocitrate is toxic because it is inhibitory to aconitase, the enzyme responsible for the conversion of citrate into czs-aconitate and then into isocitrate in the tricarboxylic acid cycle. Inhibition of aconitase results in citrate accumulation. The cycle stops for lack of metabolites, leading to disruption of energy metabolism. 

Tai, Y., But, P., Young, K., and Lau, C. 1992. Cardiotoxicity after accidental herb-induced aconite poisoning. Lancet 340, 1254-1256. 

Many of the poisons used more recently. Arsenic, cyanide, strychnine, opium, atropine, aconite and heavy metals, were also described in... 

Serious symptoms are seldom seen. The most common symptoms are stomach troubles, stomach pains, vomiting, diarrhoea, that can lead to loss of fluid. More specific problems might occur with certain plant poisonings for instance dilation of the pupil, redness of the skin, heart palpitations in poisoning with atropine, a component of Belladonna and Datura-species, disturbances in cardiac rhythm (Digitalis, Nerium, Aconite), convulsions (Aconite, Cowbane) these are among the most poisonous species of plants. 

A paragraph is given to herbal medicine as practiced in Tibet, with the comment that many of their substances have bad side effects, the same as for conventional chemotherapy. Some of these substances are aconite (Aconitum ferrox), which is very poisonous, sweet flag or calamus (Acorns calamus), bitumen, and arsenic, all of which require close monitoring. 

Aconite Prom the Aconltum napellus. Monk s hood wolf bane. Roots yield a famous alkaloldal poison and sedative. 

Toxicology.—Aconite and aconitine have been the agents used iu quite a number of homicidal poisonings. 

Aconite is sometimes added to liquors in India to increase their intoxicating effect, and this has been known to lead to fatal poisoning. Numerous species of Aconitum occur in various parts of the world, varying considerably in their toxicity and alkaloidal content. Poisoning in livestock is not common, though horses have been known to crop the plant (238, 239) and cattle have been poisoned by plants thrown out of the garden in autumn (24). 

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