To study various polyhydroxy-alkaloid glycosidase inhibitors, 16 groups of 3 mice were dosed using osmotic minipumps with swainsonine (0, 0.1, 1, and 10 mg/kg/day), castanospermine, and calystegines A₃, B₂, and C₁ (1, 10, and 100 mg/kg/day). After 28 days, the mice were euthanized, necropsied, and examined using light and electron microscopy. The high-dose swainsonine–treated mice developed neurologic disease with neuro-visceral vacuolation typical of locoweed poisoning. Castanospermine- and calystegines-treated mice were clinically normal; however, high-dose castanospermine–treated mice had thyroid, renal, hepatic, and skeletal myocyte vacuolation. Histochemically, swainsonine- and castanospermine-induced vacuoles contained mannose-rich oligosaccharides. High-dose calystegine A₃–treated mice had increased numbers of granulated cells in the hepatic sinusoids. Electron microscopy, lectin histochemistry, and immunohistochemistry suggest these are pit cells (specialized NK cells). Histochemically, the granules contain glycoproteins or oligosaccharides with abundant terminal N-acetylglucosamine residues. Other calystegine-treated mice were histologically normal. These findings indicate that swainsonine produced lesions similar to locoweed, castanospermine caused vacuolar changes with minor changes in glycogen metabolism, and only calystegine A₃ produced minimal hepatic changes. These also suggest that in mice calystegines and castanospermine are less toxic than swainsonine, and as rodents are relatively resistant to disease, they are poor models to study such induced storage diseases.

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.