title: Glucuronidation, a new metabolic pathway for pyrrolizidine alkaloids.
abstract: Pyrrolizidine alkaloids (PAs) possess significant hepatotoxicity to humans and animals after metabolic activation by liver P450 enzymes. Metabolism pathways of PAs have been studied for several decades, including metabolic activation, hydroxylation, N-oxidation, and hydrolysis. However, the glucuronidation of intact PAs has not been investigated, although glucuronidation plays an important role in the elimination and detoxication of xenobiotics. In this study, PAs glucuronidation was investigated, and three important points were found. First, we demonstrated that senecionine (SEN)-a representative hepatotoxic PA-could be conjugated by glucuronic acid via an N-glucuronidation reaction catalyzed by uridine diphosphate glucuronosyl transferase in human liver microsomes. Second, glucuronidation of SEN was catalyzed not only by human but also other animal species and showed significant species differences. Rabbits, cattle, sheep, pigs, and humans showed the significantly higher glucuronidation activity than mice, rats, dogs, and guinea pigs on SEN. Kinetics of SEN glucuronidation in humans, pigs, and rabbits followed the one-site binding model of the Michaelis-Menten equation, while cattle and sheep followed the two-sites binding model of the Michaelis-Menten equation. Third, besides SEN, other hepatotoxic PAs including monocrotaline, adonifoline, and isoline also underwent N-glucuronidation in humans and several animal species such as rabbits, cattle, sheep, and pigs.
authors.affiliation: The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai 201210, China.
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: He
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Liu
authors.forename: Jiang-Wei
authors.initials: JW
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Alan
authors.initials: A
authors.lastname: Fong
authors.forename: Ai-Zhen
authors.initials: AZ
authors.lastname: Xiong
authors.forename: Yan-Liu
authors.initials: YL
authors.lastname: Lu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Chang-Hong
authors.initials: CH
authors.lastname: Wang
authors.forename: Zheng-Tao
authors.initials: ZT
authors.lastname: Wang
mesh_terms: D000818:Animals; D002417:Cattle; D006224:Cricetinae; D004285:Dogs; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*
chemical_list: D011763:Pyrrolizidine Alkaloids; D014535:Uridine Diphosphate Glucuronic Acid; C009237:senecionine