Abstract
Pyrrolizidine alkaloids (PAs) are toxic plant constituents occurring often in their N-oxide form. This raises the question on the relative potency (REP) values of PA-N-oxides compared to the corresponding parent PAs. The present study aims to quantify the in vivo REP value of riddelliine N-oxide compared to riddelliine using physiologically based kinetic (PBK) modelling, taking into account that the toxicity of riddelliine N-oxide depends on its conversion to riddelliine by intestinal microbiota and in the liver. The models predicted a lower Cmax and higher Tmax for the blood concentration of riddelliine upon oral administration of riddelliine N-oxide compared to the Cmax and Tmax predicted for an equimolar oral dose of riddelliine. Comparison of the area under the riddelliine concentration–time curve (AUCRID) obtained upon dosing either the N-oxide or riddelliine itself revealed a ratio of 0.67, which reflects the in vivo REP for riddelliine N-oxide compared to riddelliine, and appeared to closely match the REP value derived from available in vivo data. The models also predicted that the REP value will decrease with increasing dose level, because of saturation of riddelliine N-oxide reduction by the intestinal microbiota and of riddelliine clearance by the liver. It is concluded that PBK modeling provides a way to define in vivo REP values of PA-N-oxides as compared to their parent PAs, without a need for animal experiments.
Highlights
Pyrrolizidine alkaloids (PAs) are toxic plant secondary metabolites that may negatively impact human and animal health through accidental consumption of contaminated food
Using the scaling factor of 0.0164 as fraction of feces to bodyweight expressed in g feces g bw−1 (Hoskins and Zamcheck 1968; Wang et al 2020) and a body weight of 250 g, the Vmax was converted to an in vivo Vmax expressed in μmol h−1 per rat, which was the value used in the physiologically based kinetic (PBK) model
relative potency (REP) value of 0.64 was best predicted when using the kinetic data obtained in aerobic liver S9 incubations and the fact that the liver is unlikely to be anaerobic but known to contain on average about 3 mM oxygen (Boobis and Powis 1974), it was concluded that kinetic parameters from aerobic liver S9 incubations are preferred to predict REP values of pyrrolizidine N-oxide s relative to their parent PAs
Summary
Pyrrolizidine alkaloids (PAs) are toxic plant secondary metabolites that may negatively impact human and animal health through accidental consumption of contaminated food. PAs and PA-N-oxide s with 1,2-unsaturated necine bases are toxic Archives of Toxicology activated by cytochromes P450 (CYP450) to form pyrrole esters known as dehydropyrrolizidine alkaloids (DHPAs), [(±)6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine] (DHP), and other reactive metabolites (Chu et al 1993; Fu et al 2001, 2004). These metabolites react with cell proteins and DNA, forming pyrrole adducts (Chan et al 2003; Fu et al 2010). Pyrrole-protein and pyrrole-DNA adducts may cause hepatotoxicity (Yang et al 2016) and genotoxicity (Fu et al 2004; Yang et al 2001)
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