title: Comparative Study of Hepatotoxicity of Pyrrolizidine Alkaloids Retrorsine and Monocrotaline.
abstract: Many pyrrolizidine alkaloids (PAs) can cause liver injury in animals and humans. Different hepatotoxic PAs can produce similar hepatotoxic effects, but the degree of their toxicities may vary widely. Retrorsine (RTS) and monocrotaline (MCT) share the same core structure (retronecine) and similar metabolic activation pathway. RTS and MCT both produced liver injury, but the former was more hepatotoxic than the latter. Enzyme kinetic study demonstrated that the value of Vmax/Kmfor RTS was 5.5-fold larger than that of MCT. Additionally, RTS produced higher levels of pyrrole-glutathione (GSH) conjugates and protein covalent binding than MCT at the same dose. Furthermore, RTS induced significant hepatic GSH depletion but MCT did little. This comparative study provides clear evidence that the generation of the reactive pyrrolic intermediates plays a critical role in PA-induced hepatotoxicity.
authors.affiliation: Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.affiliation: Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
authors.forename: Xiucai
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
authors.forename: Jiang
authors.identifier: 0000-0002-0340-0275
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D016686:Monocrotaline / Q000633:toxicity*; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*
chemical_list: D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D005978:Glutathione; C003300:retrorsine