Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach.
Arch Toxicol
; 94(9): 3281-3295, 2020 09.
Article
en En
| MEDLINE
| ID: mdl-32518961
ABSTRACT
The aim of the present study was to use an in vitro-in silico approach to predict the in vivo acute liver toxicity of monocrotaline and to characterize the influence of its metabolism on its relative toxic potency compared to lasiocarpine and riddelliine. In the absence of data on acute liver toxicity of monocrotaline upon oral exposure, the predicted dose-response curve for acute liver toxicity in rats and the resulting benchmark dose lower and upper confidence limits for 10% effect (BMDL10 and BMDU10) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL10 value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL10-BMDU10 of 1.1-4.9 mg/kg bw/day also matched the oral dose range of 1-3 mg PA/kg bw/day at which adverse effects in human are reported. A comparison to the oral toxicity of the related pyrrolizidine alkaloids (PAs) lasiocarpine and riddelliine revealed that, although in the rat hepatocytes monocrotaline was less toxic than lasiocarpine and riddelliine, due to its relatively inefficient clearance, its in vivo acute liver toxicity was predicted to be comparable. It is concluded that the combined in vitro-PBK modeling approach can provide insight in monocrotaline-induced acute liver toxicity in rats, thereby filling existing gaps in the database on PA toxicity. Furthermore, the results reveal that the kinetic and metabolic properties of PAs can vary substantially and should be taken into account when considering differences in relative potency between different PAs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Toxinas Biológicas
/
Monocrotalina
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Arch Toxicol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Países Bajos