Hepatic pyrrolizidine alkaloid toxicity

Other significant experiments have corroborated the metabolic pyrrole hypothesis. When cells other than those capable of microsomal oxidation (i.e., cells other than liver) were incubated with pyrrolizidine alkaloids toxicity was not observed. However when these cells were exposed to synthetically prepared necine pyrroles, severe mitotic inhibition was observed. The chemical stability of the pyrrolic alkaloids is much less than that of the corresponding necine pyrroles and the former have not been detected Ija vivo. However when synthetic monocrotaline pyrrole was injected into the mesenteric vein of rats it produced the lesions typical of pyrrolizidine alkaloid poisoning portal vascular degeneration, hepatic necrosis, and inhibition of hepatocyte mitosis (63,64). Injected into the jugular veins of rats and dogs... 

Because 1,4-dichlorobenzene is a liver toxin, it probably can interact with other chemicals that are liver toxicants. These toxicants are many, and include ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc ), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or S5mergistic effects. 

Many pyrrolizidine alkaloids are known to produce pronounced hepatic toxicity and there are many recorded cases of livestock poisoning. Potentially toxic structures have 1,2-unsaturation in the pyrrolizidine ring and an ester function on the side-chain. Although themselves non-toxic, these alkaloids are transformed by mammalian liver... 

Many pyrrolizidine alkaloids are metabolized to toxic pyrrole metabolites in the liver by mixed-function oxidases. The structural and chemical features necessary for the formation of these metabolites have been discussed.77 The most important features, in addition to the 3-hydroxymethyl-3-pyrroline system, are steric hindrance to hydrolysis of the ester, lipophilic character (favouring attack by the hepatic microsomal enzymes), and the presence of a conformation that allows preferential oxidation of the pyrroline ring rather than 7V-oxidation. The alkylating activities of a series of these pyrrole derivatives have been examined.78... 

ZUCKERMAN, M STEENKAMP, V., STEWART, M.J., Hepatic veno-occlusive disease as a result of a traditional remedy confirmation of toxic pyrrolizidine alkaloids as the cause, using an in vitro technique., J. Clin. Pathol., 2002, 55, 676-679. 

Khanin, M.N. (1948) [The etiology of toxic hepatitis with ascites.] Arch. Pathol. USSR. 1, 42-47 (in Russian). From Environmental Health Criteria 80 Pyrrolizidine Alkaloids. World Health Organization, Geneva. 

Comfrey is a perennial herb used for the prevention of kidney stones nourishing and repairing bone and muscle and for the treatment of injuries such as burns and bruises. In Australia, comfrey is classified as a poison and its sales have been restricted in several regions. Many different commercial forms of comfrey are marketed, including oral and external products. Commercial comfrey is usually derived from the leaves or roots of Symphytum officinale (common comfrey). However, some products are also derived from Russian comfrey. Russian comfrey contains a very toxic pyrrolizidine alkaloid, echimidine, which is not found in common comfrey. However, common comfrey contains other hepatotoxic alkaloids, namely 7-acetylintermedine, 7-acetyllycopsamine and symphytine. The metabolites of these alkaloids are very toxic to the liver. Ridker et al. documented hepatic venocclusive disease associated with consumption of comfrey root. Long-term smdies in animals have also confirmed the carcinogenicity of comfrey in animal models. ... 

In a study of toxicity of Sri Lankan traditional medicinal herbs, Arseculer-atne and co-workers evaluated 125 commonly used medicinal plants for the occurrence of hepatotoxic pyrrolizidine alkaloids (129,130). Crotolaria juncea, C. verrucosa, and Holarrhena antidysenterica were shown to contain pyrrolizidine alkaloids by TLC. When fed to rats, these plants produced hepatic lesions compatible with the action of pyrrolizidine alkaloids. 

H. Hepatic failure. A variety of dmgs and toxins may cause hepatic injury (Table 1-29). Mechanisms of toxicity include direct hepatocellular damage (eg. Amanita phalloides mushrooms [see p 273]), metabolic creation of a hepato-toxic intermediate (eg, acetaminophen [p 66] or carbon tetrachloride [p 154]), or hepatic vein thrombosis (eg, pyrrolizidine alkaloids see Plants, p 309). 

Chen, Z., and R.-H. Huo. 2010. Hepatic veno-occlusive disease associated with toxicity of pyrrolizidine alkaloids in herbal preparations. Neth. J. Med. 68 (6) 252-260. 

The toxic metabolites of pyrrolizidine alkaloids are pyrrole derivatives produced by hepatic mixed function oxidases. These derivatives are highly reactive alkylating agents, which may act by alkylating sulphydryl groups 242, 270). In order to form these toxic pyrrolic metabolites, the alkaloids must possess 1,2-unsaturation in the necine [as in (100)], and be esterified at C-9. Substitution at the a-position of the acid and esterification of the C-7 hydroxy-group both increase the toxicity of the alkaloid. 

---