Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Abstract

Dehydropyrrolizidine alkaloid (DHPA)-producing plants have a worldwide distribution amongst flowering plants and commonly cause poisoning of livestock, wildlife, and humans. Previous work has produced considerable understanding of DHPA metabolism, toxicity, species susceptibility, conditions, and routes of exposure, and pathogenesis of acute poisoning. Intoxication is generally caused by contaminated grains, feed, flour, and breads that result in acute, high-dose, short-duration poisoning. Acute poisoning produces hepatic necrosis that is usually confirmed histologically, epidemiologically, and chemically. Less is known about chronic poisoning that may result when plant populations are sporadic, used as tisanes or herbal preparations, or when DHPAs contaminate milk, honey, pollen, or other animal-derived products. Such subclinical exposures may contribute to the development of chronic disease in humans or may be cumulative and probably slowly progress until liver failure. Recent work using rodent models suggest increased neoplastic incidence even with very low DHPA doses of short durations. These concerns have moved some governments to prohibit or limit human exposure to DHPAs. The purpose of this review is to summarize some recent DHPA research, including in vitro and in vivo DHPA toxicity and carcinogenicity reports, and the implications of these findings with respect to diagnosis and prognosis for human and animal health.

Keywords: DHPA; PA; alkaloids; carcinogenesis; dehydropyrrolizidine; pyrrolizidine; pyrrolizidine alkaloid-induced cytotoxicity; toxic hepatopathy; toxic plant.

Figure 1

The top row contains the general structure of a non-toxic pyrrolizidine alkaloid. The middle two structures are toxic dehydropyrrolizidine alkaloids, heliotridine and retronecine, with a 1,2 unsaturation that is characteristic of toxic alkaloids. The top right structure is, a dehydroxypyrrolizidine alkaloid N-oxide. The second line contains dehydroxypyrrolizidine alkaloid, riddelliine, which is a macrocyclic diester retronecine base alkaloid. The center structure is a “pyrrolic” riddelliine, dehydroriddelliine, or didehydroxypyrrolizidine alkaloid. The last structure on the right is a “pyrrolic” metabolite or macromolecule adduct.

Figure 2

California White chick dosed with riddelliine at 0.26 mMol/kg BW/day for 10 days. Notice the extensive ascites (a) with mild fibrinous pleuritis (p) and the extremely small and firm liver (l).

Figure 3

Photomicrograph of the liver from a California White chick dosed with riddelliine at 0.26 mMol/kg BW/day for 10 days. Notice the massive hepatocellular necrosis (n) with the collapse of hepatic cords with hemorrhage (h). There is minimal periportal inflammation, edema, and early proliferation of ovalocytes (arrow).

Figure 4

Photomicrograph of the liver of a California White chick dosed with riddelliine at 0.4 mMol/kg BW/ for 10 days. Notice the enlarged hepatocytes (arrow) with large nuclei and abundant heterochromatin (most likely developing megalocytes). There is also periportal inflammation and fibrosis (*) with oval cell and biliary epithelial proliferation (bh).

Figure 5

Structures of dehydropyrrolizidine alkaloids that were ranked in this review. Lasiocarpine (heliotridine diester), seneciphylline and senecionine (retronecine macrocyclic diester), heliotrine (heliotridine monoester), riddelliine, monocrotaline, riddelliine N-oxide (retronecine macrocyclic diesters), intermedine, lycopsamine, lycopsamine N-oxide (heliotridine monoester), and senecionine N-oxide (retronecine macrocyclic diester).