Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach
Wesseling S., Suparmi S., Rietjens I.M.C.M.
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 (BMDL<inf>10</inf> and BMDU<inf>10</inf>) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL<inf>10</inf> value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL<inf>10</inf>–BMDU<inf>10</inf> 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.
Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice
Feng C.-C., Gao M., Gong L.-K., Li C.-G., Li C.-Z., Luan Y., Qi X.-M., Ren J., Yao J.
Comparative Study of Hepatotoxicity of Pyrrolizidine Alkaloids Retrorsine and Monocrotaline
Guo X., Huang W., Li W., Peng Y., Sun Y., Yang X., Zheng J., Zheng J.
Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat
Huxtable R.J., Yan C.C.
The Relationship Between the Concentration of the Pyrrolizidine Alkaloid Monocrotaline and the Pattern of Metabolites Released from the Isolated Liver
Huxtable R.J., Yan C.C.
Pyrrolizidine Alkaloid Secondary Pyrrolic Metabolites Construct Multiple Activation Pathways Leading to DNA Adduct Formation and Potential Liver Tumor Initiation
Chen S., Fu P.P., He X., Ma L., Xia Q.
Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity
Cai L., Doerge D.R., Fu P.P., Lin G., Von Tungeln L.S., Xia Q., Zhao Y.
Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding
Jones R., Sohal B., Waters N.J., Williams G.
The comparative pharmacokinetics of two pyrrolizidine alkaloids, senecionine and adonifoline, and their main metabolites in rats after intravenous and oral administration by UPLC/ESIMS
Cheng X., Cheng X., Gao J., He Y., He Y., Li Y., Ma Y., Wang C., Wang C., Wang Z., Wang Z., Xiong A., Xiong A., Yang L., Yang L.
The action of cytochrome p450 enzymes and flavin-containing monooxygenases on the N-oxide of pyrrolizidine alkaloid monocrotaline
Wang C., Wang J., Wang Z., Yang L.
Development and validation of a higher-throughput equilibrium dialysis assay for plasma protein binding
Morrison D., Mortishire-Smith R., Nelis P., Sysmans L., van Liempd S.
Archives of Toxicology
Journal of Communicable Diseases
Planta Medica
Acta Biomaterialia
Toxicology
Frontiers in Pharmacology
