John A. Edgar

Hepato- and pneumotoxicity of pyrrolizidine alkaloids and derivatives in relation to molecular structure.

62 pyrrolizidine alkaloids and derivatives have been screened for acute and chronic hepato- and pneumotoxicity by the single dose method previously described. This procedure is satisfactory for the compounds of medium to high hepatotoxicity but failed to detect toxicity in certain other compounds of known, low hepatotoxicity. New findings significant in relation to hepatotoxicity are as follows: (i) On a molar basis, diesters of heliotridine and retronecine are about 4 times as toxic as the respective mono-esters and heliotridine esters are 2-4 times as toxic as retronecine esters. (ii) Crotanecine esters are less toxic than retronecine esters, and the 6,9-diester madurensine, 2-4 times less toxic than the 7,9-diester anacrotine (the difference being ascribed to there being only one reactive alkylating centre in the toxic metabolite from madurensine). (iii) Hepatotoxicity was confirmed for 7-angelylheliotridine but not observed for 9-angelyheliotridine and 7- and 9-angelylretronecine. (iv) Other significant compounds failing to induce hepatotoxicity were 9-pivalyl- and 7,9-dipivalyheliotridine, the alpha- and beta-epoxides of monocrotaline, 7-angelyl-1-methylenepyrrolizidine and the methiodides of monocrotaline and senecionine. The following compounds are readily converted by rat liver microsomes in vitro into dehydroheliotridine (or dehydroretronecine): 7- and 9-angelyheliotridine, 7- and 9-angelylretronecine, 7,9-dipivalylheliotridine and otosenine. 7,9-Divalerylheliotridine, the alpha- and beta-epoxides of monocrotaline, and retusamine yield pyrrolic metabolites more slowly. The preparation and characterisation of several alkaloid derivatives are described. Chronic lung lesions were produced by most compounds which gave chronic liver lesions, although a higher dose was required in some instances. This requirement may sometimes mean that chronic lung lesions cannot be induced because of the intervention of acute or peracute deaths. Apart from this factor, structure activity requirements for pneumotoxicity are the same as for hepatotoxicity, consistent with their being both caused by the same toxic metabolites.

PYRROLIZIDINE ALKALOIDS AS ALKYLATING AND ANTIMITOTIC AGENTS

The pyrrolizidine alkaloids occur most frequently in the plant families Compositae (tribe Senecioneae), Boraginaceae (subfamilies Heliotropioideae and Boraginoideae), and Leguminosae (genus Crotaluria), but in recent years they have been found also in the families Celastraceae, Gramineae, Orchidaceae, Rhizophoraceae, Santalaceae, and Sapotaceae, as well as in the genus Eupatorium, which belongs to a different section of the Compositae. Depending on the dose level, the hepatotoxic alkaloids produce peracute, acute, or chronic toxic effects in animals, the chronic syndrome being the one usually encountered in natural occurrences of pyrrolizidine poisoning. The characteristic feature of the chronic syndrome is a megalocytosis of the liver in which the liver becomes composed of a small number of giant cells. This lesion appears to result from a long-lasting antimitotic effect combined with an increased rate of cell death, which gives a stimulus to liver growth.

Toxicity of pyrrolizidine alkaloids to humans and ruminants

Abstract1,2-dehydro pyrrolizidine ester alkaloids (PA) are toxic for human and livestock. The PAs undergo a metabolic toxication process in the liver which is the first target organ for PA poisoning. World-wide many episodes of PA intoxications have been reported involving humans as well as ruminants. This intoxication is not only related to the amount and duration of the exposure to PAs but also to species, age and gender. Besides the metabolic toxification, detoxication processes are also important. The paper discusses the toxification and detoxication processes and gives an overview about PA poisoning cases in humans and ruminants.

Pyrrolizidine alkaloids in food: a spectrum of potential health consequences.

Contamination of grain with 1,2-dehydropyrrolizidine ester alkaloids (dehydroPAs) and their N-oxides is responsible for large incidents of acute and subacute food poisoning, with high morbidity and mortality, in Africa and in central and south Asia. Herbal medicines and teas containing dehydroPAs have also caused fatalities in both developed and developing countries. There is now increasing recognition that some staple and widely consumed foods are sometimes contaminated by dehydroPAs and their N-oxides at levels that, while insufficient to cause acute poisoning, greatly exceed maximum tolerable daily intakes and/or maximum levels determined by a number of independent risk assessment authorities. This suggests that there may have been cases of disease in the past not recognised as resulting from dietary exposure to dehydroPAs. A review of the literature shows that there are a number of reports of liver disease where either exposure to dehydroPAs was suspected but no source was identified or a dehydroPA-aetiology was not considered but the symptoms and pathology suggests their involvement. DehydroPAs also cause progressive, chronic diseases such as cancer and pulmonary arterial hypertension but proof of their involvement in human cases of these chronic diseases, including sources of exposure to dehydroPAs, has generally been lacking. Growing recognition of hazardous levels of dehydroPAs in a range of common foods suggests that physicians and clinicians need to be alert to the possibility that these contaminants may, in some cases, be a possible cause of chronic diseases such as cirrhosis, pulmonary hypertension and cancer in humans.

Structure and toxicity of the alkaloids of Russian comfrey ( Symphytum x uplandicum Nyman), a medicinal herb and item of human diet

Eight pyrrolizidine alkaloids of hepatotoxic type have been indentified in leaves ofSymphytum × uplandicum The combined alkaloids exhibit chronic hepatotoxicity in rats.

Isolation of a lactone, structurally related to the esterifying acids of pyrrolizidine alkaloids, from the costal fringes of male Ithomiinae

Adult male Ithomiinae feed at plants containing pyrrolizidine alkaloids. Certain species secrete on hairs of the “costal fringe,” a specialized organ on their hindwings, a novel γ-lactone structurally related to the unusual branched-chain acids that are unique to these alkaloids.

Hepatotoxic Pyrrolizidine Alkaloids in Pollen and Drying-Related Implications for Commercial Processing of Bee Pollen

Using HPLC-ESI-MS, several saturated and 1,2-dehydropyrrolizidine alkaloids were detected, mainly as their N-oxides, in fresh pollen collected from flowers of the pyrrolizidine alkaloid-producing plants Echium vulgare, E. plantagineum, Senecio jacobaea, S. ovatus, and Eupatorium cannabinum, and/or pollen loads from bees (bee pollen) that foraged on those plants. A major alkaloidal metabolite in S. ovatus was tentatively identified, using its mass spectrometric data and biogenic considerations, as the previously unreported, saturated alkaloid, 2-hydroxysarracine. Heating had very little effect on the 1,2-dehydropyrrolizidine alkaloids and their N-oxides from a variety of sources. Considered in conjunction with international concerns about the adverse effects of these alkaloids, the results strongly indicate a need for monitoring pollen supplies intended for human consumption, at least until conditions for processing and/or selection are clearly defined such as to significantly reduce the hepatotoxic (and potentially carcinogenic and genotoxic) pyrrolizidine alkaloid content of bee pollen.

Dihydropyrrolizine derivatives in the ‘hair-pencil’ secretions of danaid butterflies

Von 6 australischen Schmetterlingsarten der Untergruppe Danainae enthielten 4 Dihydropyrrolizine, dazu das bekannte Keton (I) und 2 verwandte Substanzen (II and III).

Pyrrolizidine alkaloids inDanaus plexippus L. andDanaus chrysippus L.

Danaus plexippus L. andDanaus chrysippus L. have been found to store pyrrolizidine alkaloids obtained from adult food plants and it is suggested that the alkaloids contribute to the unpalatability of the butterflies to potential predators.

Dihydropyrrolizine secretions associated with coremata ofUtetheisa moths (family Arctiidae)

Die Duftorgane der männlichen BärenspinnerUtetheisa pulchelloides undU. lotrix (Fam. Arctiidae) scheiden Dihydropyrrolizine aus, die im Typ den Pheromonen von Schmetterlingen der Subfamilie Danainae (Fam. Papilionidae) gleichen. Wahrscheinlich handelt es sich um Derivate von Pyrrolizidin-Alkaloiden, die in den Wirtsplanzen der Raupen in hoher Konzentration vorkommen.