Abstract
Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) known to cause liver toxicity. The aim of this study was to predict the inter-species and inter-ethnic human differences in acute liver toxicity of lasiocarpine and riddelliine using physiologically based kinetic (PBK) modelling based reverse dosimetry of in vitro toxicity data. The concentration–response curves of in vitro cytotoxicity of lasiocarpine and riddelliine defined in pooled human hepatocytes were translated to in vivo dose–response curves by PBK models developed using kinetic data obtained from incubations with pooled tissue fractions from Chinese and Caucasian individuals, providing PBK models for the average Chinese and average Caucasian, respectively. From the predicted in vivo dose–response curves, the benchmark dose lower and upper confidence limits for 5% effect (BMDL5 and BMDU5) were derived and subsequently compared to those previously obtained in rat to evaluate inter-species differences. The inter-species differences amounted to 2.0-fold for lasiocarpine and 8.2-fold for riddelliine with humans being more sensitive than rats. The inter-ethnic human differences varied 2.0-fold for lasiocarpine and 5.0-fold for riddelliine with the average Caucasian being more sensitive than the average Chinese. In conclusion, the present study provides the proof-of-principle to predict inter-species and inter-ethnic differences in in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity data with PBK modelling-based reverse dosimetry.
Highlights
Lasiocarpine and riddelliine (Fig. 1) are chemicals belonging to the group of pyrrolizidine alkaloids (PAs) which are important secondary metabolites of approximately 6000 plant species distributed around the world (Smith and Culvenor 1981)
The results show that rat hepatocytes are more sensitive to lasiocarpine and riddelliine than the HepaRG and human hepatocytes, with the IC50 of lasiocarpine in rat hepatocytes being 20- and 2-fold lower than the IC50 in HepaRG and human hepatocytes, respectively and the IC50 of riddelliine in rat hepatocytes being 22- and 7-fold lower than the IC50 for riddelliine in HepaRG and human hepatocytes, respectively
The physiologically based kinetic (PBK) model developed in the present study describes the kinetics of lasiocarpine and riddelliine and not of their metabolites, since we assume that the acute liver toxicity of lasiocarpine and riddelliine can be modelled based on cytotoxicity data of the parent compound provided that the in vitro model used contains the adequate enzymes required for their bioactivation to hepatotoxic metabolites
Summary
Lasiocarpine and riddelliine (Fig. 1) are chemicals belonging to the group of pyrrolizidine alkaloids (PAs) which are important secondary metabolites of approximately 6000 plant species distributed around the world (Smith and Culvenor 1981). Human exposure to lasiocarpine and riddelliine may result from the consumption of contaminated food staples, plant food supplements, herbal medicines, herbal teas, honey and milk (EFSA 2011, 2017). A 2-year National Toxicology Program (NTP) study testing the genotoxicity and carcinogenicity of lasiocarpine and riddelliine showed that these PAs are carcinogenic and genotoxic compounds (Chan et al 2003; NTP 1978, 2003). Riddelliine induced a high incidence of liver hemangiosarcoma in both male (43 out of 50 rats) and female rats (38 out of 50 rats) at 0.7 mg/kg bw/day (Chan et al 2003; NTP 1978, 2003). The International Agency for Research on Cancer (IARC) classified these alkaloids in Group 2B, potentially carcinogenic to humans (IARC 2017)
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