ReviewHepatic sinusoidal-obstruction syndrome: toxicity of pyrrolizidine alkaloids
Introduction
The main hepatic injury of Pyrrolizidine alkaloids (PA) is sinusoidal-obstruction syndrome (SOS), which is a major medical complication of bone marrow transplantation [1]. PA are constitutively expressed in several plant families, including about 3% of the world's flowering plants. PA are toxic to the liver and/or lungs in humans. Therefore, individuals consuming herbal remedies or herbal teas containing PA are at risk of developing acute and/or chronic liver and lung toxicity. These include acute liver failure, cirrhosis, pneumonitis, pulmonary hypertension and heart failure.
Section snippets
Botany
PA are constitutively expressed in species of highly restricted phlylogenetic distribution within the angiosperms [2]. The vast majority of PA are found in the plant families Compositae (Asteraceae), Boraginaceae, Leguminosae (Fabaceae), Apocynaceae and Orchidaceae [3], [4]. More than 300 PA have been identified in over 6000 plants of the Compositae, Boraginaceae and Leguminosae families [4]. Of particular importance regarding livestock and human toxicity are the Senecio, Crotalaria,
Pharmacology/metabolism
The structural characteristics of the various PA determines the variable degrees of toxicity to livestock and humans [5]. Herbal remedies that contain PA are derived among others from comfrey, borage, purging buckthorn, coltsfoot, groundsel, buglosis, plague root and Gromwell/Millet [4], [6], [37], [38], [39], [40], [41], [42], [43]. At least for the induction of hepatotoxicity, the PA should contain a 1.2 unsaturated necine base, which is usually esterified to necic acid [19]. Because the free
Hepatic injury
PA extracted and purified from Russian comfrey (Symphytum×uplandicum) induced a dose-dependent liver damage when fed to rats [14]. This plant has at least eight PA [94]. Animals developed various degrees of loss of perivenular hepatocytes with extravasation of red blood cells into perivenular spaces and into the perisinusoidal space of Dissé. Other hepatocytes displayed swelling and necrosis contributing to sinusoidal dilation [14]. Pericellular reticulin fibers (representing predominantly
Carcinogenesis
Pyrrolic PA, but not the necine base, are capable of crosslinking proteins to DNA in a cell-free system [55]. The pyrroles of senecionine, monocrotaline, seneciphylline and riddelliine induce potent DNA crosslinks. In cells or isolated nuclei exposed to PA, the principal proteins crosslinked to DNA were 40–60 kDa in molecular weight and acidic [55]. Loss of function of the critical tumor suppressor p53, secondary to mutations or deletions, occurs in many human cancer [141], and mice with a
Pulmonary toxicity
Some PA are capable of inducing pulmonary hypertension and right ventricular hypertrophy in many different animal species [101]. The Crotalaria alkaloids, monocrotaline (MCT) and fulvine [116], [117], [155] and the Senecio alkaloid, seneciphylline [156] are the most commonly used in experimental pulmonary hypertension. The toxic pyrrole derivatives, which are byproducts of hepatic metabolism [19], are transported in the blood to the lung [6]. Administration of pneumotoxic [3H]-labeled PA
Conclusion
An enhanced predisposition towards PA-induced toxicity may be genetic or acquired through the variable hepatic metabolism of PA. For example, the concomitant use of some medications could increase the toxicity of PA. External absorption of PA from skin and hair products could occur, with the consequent liver and/or lung toxicity, if the skin or the scalp is damaged.
In addition, PA are carcinogenic to animals, including the development of hepatocellular and skin squamous cell carcinomas as well
Acknowledgements
This study was supported in part by the National Institutes of Health, the Food and Drug Administration and the Department of Veterans Affairs.
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