By: Esther Hegt and Dr. Pieter B. Pelser ( University of Canterbury- Biological Sciences, Christchurch, New Zealand)

In plants, pyrrolizidine alkaloids (PAs) are mostly stored in their non-toxic form (as pyrrolidizine N-oxides). Figure 1a shows an example of a PA called heliotrine. The blue ‘N’ in the heliotrine molecule is a nitrogen atom, which can be oxidized. This means that an oxygen atom will bind with the nitrogen. So, this in an example of an N-oxide; in this case heliotrine N-oxide (Fig. 1b).N-oxides are water soluble and do not dissolve well in fat. Because the inner surface of intestines contains a relatively high concentration of fat, PAs have a hard time passing the intestine wall when they are in their N-oxide form. However, PAs don’t usually stay in their N-oxide form in the intestines: they are reduced, which means that the oxygen molecule splits off from the nitrogen. The resulting molecule (Fig. 1a) can be absorbed through the intestine wall and will end up in the bloodstream, which passes through the liver. In the liver, three things can happen to a PA molecule. 1) It can be hydrolyzed, which will result in a molecule that is not toxic (Fig. 1c). 2) It may also be oxidized again resulting in a water soluble N-oxide (Fig. 1b), which will be excreted by the body, 3) but it may also be dehydrogenized during several steps into the molecule shown in (Fig. 1d) (dehydroheliotrine). The intermediate molecules that are formed during the dehydrogenization process are very toxic, because they can damage different kinds of tissue. Because these intermediate molecules are quickly transferred into other molecules, they cannot be found in samples taken from an animal. Only the presence of dehydro-PAs can be shown. Although these dehydro-PAs are more stable than the molecules that are formed in the process in which N-oxides are transferred into dehydro-PA's, they can also react with a lot of other molecules. This is because it contains a double bond (the = in the double ring of the PA molecule), which makes it easier for this molecule to bind to oxidize other molecules, damaging these.

1a)                                                                           1b)

1c)                                                                          1d)

In collaboration with Merijn Roos (veterinarian at the Faculteit Diergeneeskunde in Utrecht).

Stewart, M. J. & V. Steenkamp. 2001. Pyrrolizidine poisoning: a neglected area in human toxicology. Therapeutic Drug Monitoring 23: 698-708.