Structure-dependent hepato-cytotoxic potencies of selected pyrrolizidine alkaloids in primary rat hepatocyte culture

Food Chem Toxicol. 2020 Jan:135:110923. doi: 10.1016/j.fct.2019.110923. Epub 2019 Oct 28.

Abstract

Contamination of food, feed and herbal medicines with plants containing pyrrolizidine alkaloids (PA) leads to measurable amounts of PA in many products. Since a number of PA are hepatotoxic in humans and animals and hepato-carcinogenic in animal experiments, the assessment of the relative toxic potencies of widely occurring PA contaminants warrants detailed investigation. Here, we studied the hepato-cytotoxic potencies of a number of relevant PA congeners in rat hepatocytes in primary culture. It was found that cyclic and open di-esters were much more toxic than mono-esters. Furthermore, the hepatocellular levels of cytochrome P450-catalyzed 7-benzoxyresorufin O-dealkylase (BROD) activity decreasing over time in culture, played an important role for activation of PA into cytotoxic metabolites. With a highly toxic PA (lasiocarpine), inhibition of BROD activity with ketoconazole markedly reduced toxicity while this was not obvious with the less toxic congener lycopsamine. Depletion of cellular glutathione with buthionine sulfoximine had no significant influence on the effects of highly toxic PA whereas it slightly increased toxicity of less potent congeners. Overall, our data partially confirm previously published structure-dependent interim Relative Potency (iREP) factors although for echimidine and monocrotaline in particular, substantial deviations were found, possibly due to specific toxicokinetic properties of these congeners.

Keywords: Cytotoxicity; Liver toxicity; Pyrrolizidine alkaloids; Rat hepatocytes; Relative potency.

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / metabolism
  • Glutathione / metabolism
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Male
  • Molecular Structure
  • Primary Cell Culture
  • Pyrrolizidine Alkaloids / chemistry
  • Pyrrolizidine Alkaloids / toxicity*
  • Rats, Wistar

Substances

  • Pyrrolizidine Alkaloids
  • Cytochrome P-450 Enzyme System
  • 7-benzoxyresorufin-O-dealkylase
  • Glutathione