Intrinsic relative potency of a series of pyrrolizidine alkaloids characterized by rate and extent of metabolism
2019
Lester, Cathy | Troutman, John | Obringer, Cindy | Wehmeyer, Kenneth | Stoffolano, Peter | Karb, Michael | Xu, Yan | Roe, Amy | Carr, Greg | Blackburn, Karen | Mahony, Catherine
1,2-Unsaturated pyrrolizidine alkaloids (PAs) are sometimes present in foods or herbal supplements/medicines as impurities and pose potential concerns for liver genotoxicity/carcinogenicity. PAs display a strong structure toxicity relationship, however, current regulatory approaches to risk assessment take the precautionary approach of assuming all PAs display the same potency as the most toxic congeners lasiocarpine (LAS) and riddelliine (RID). Here we explore the relative potencies of a series of structurally diverse PAs by measuring DNA adduct formation in vitro in a rat sandwich culture hepatocyte (SCH) cell system. The adducts generated are consistent with those identified in vivo as biomarkers of PA exposure and potential liver-tumor formation. DNA reactive PAs require metabolic activation to form intermediates that bind DNA, therefore, adduct formation is a direct reflection of reactive metabolite formation. Since the area under the concentration versus time curve (AUC) for the depletion of parent PA from the extracellular media is a measure of PA exposure, the ratio of adducts/AUC provides a measure of hepatocyte exposure to DNA-binding metabolites corresponding to an intrinsic potency for DNA adduct formation. Intrinsic potencies relative to potencies for LAS compare well with existing relative potency data further affirming that PA toxicity varies considerably with chemical structure.
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