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.

Preincubation format for a sensitive immunochromatographic assay for monocrotaline, a toxic pyrrolizidine alkaloid

“…Monocrotaline (MCT) is a toxic compound that belongs to the 1,2‐dehydropyrrolizidine alkaloid (DHPA) group (Figure ). Cereal grains, honey, and herbs are often contaminated with DHPAs, and exposure(s) to these compounds result in various toxicities, including acute hepatitis, gastroenteritis, pulmonary vasculitis and hypertension . In addition, there is evidence from animal models that MCT is carcinogenic upon long‐term exposure .…”

“…Other similar compounds to MCT in the DHPA class, including retrorsine, senecionine, and heliotrine, are known to be poisonous for humans and livestock. The chemical structure of DHPA contains 1,2‐unsaturation, which is essential for toxicity . DHPAs share common mechanisms of metabolic activation and toxicity.…”

“…Oxidation by the cytochrome P450 monooxygenase enzyme forms a toxic pyrrolic metabolite, which is highly reactive to cellular proteins and nucleic acids. This metabolite leads to damage in the liver, lungs, kidneys, and gastrointestinal tract . Both acute and chronic DHPA toxicity are well‐known.…”

“…toxicity. 3 DHPAs share common mechanisms of metabolic activation and toxicity. Oxidation by the cytochrome P450 monooxygenase enzyme forms a toxic pyrrolic metabolite, which is highly reactive to cellular proteins and nucleic acids.…”

“…This metabolite leads to damage in the liver, lungs, kidneys, and gastrointestinal tract. 3 This alkaloid is present in various species of flowering plants, 9 which include the genera Crotalaria, Senecio, and Symphytum. MCT is found mainly in the Crotalaria genus.…”