Pyrrolizidine alkaloids detoxification

HUAN, J.-Y., MIRANDA, C.L., BUHLER, D.R., CHEEKE, P.R., The roles of CYP3A and CYP2B isoforms in hepatic bioactivation and detoxification of the pyrrolizidine alkaloid senecionine in sheep and hamsters. Toxicol. Appl. Pharmacol., 1998,151,229-235. 

NAUMANN, C., HARTMANN, T., OBER, D., Evolutionary recruitment of a flavin-dependent monooxygenase for the detoxification of host plant-acquired pyrrolizidine alkaloids in the alkaloid-defended arctiid moth Tyria jacobaeae. Proc. Natl. Acad. Sci. U. S. A., 2002,99, 6085-6090. 

Both liver and kidney systems are affected by a variety of secondary metabolites, and the pyrrolizidine alkaloids have been discussed earlier (Tables IV and V). The alkaloids are activated during the detoxification process, and this can lead to liver cancer. Also, many other enzyme or metabolic inhibitors (e.g., amanitine), discussed previously, are liver toxins. 

Additional studies have shown that the oxidation of alkaloid to its N-oxide occurs and competes with pyrrole formation. N-oxides when administered intravenously to rats or when treated with liver microsomal enzymes are not converted to pyrroles. Hence they are non-toxic in the liver, and, by their highly hydrophilic nature, provide a pathway for detoxification. When administered orally to rats and sheep however, N-oxides are converted in the rumen (sheep) or gut (rats) to the parent alkaloids which are then metabolized in the liver causing the normal toxic sequelae. The toxicity (or lack thereof) of the pyrrolizidine N-oxides depends on whether or not they are reduced vivo before reaching the liver (61). After intravenous administration of indicine N-oxide to human cancer patients, free alkaloid has been detected in the blood and subsequent liver damage has been observed (55). 

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