7-半胱氨酸-吡咯共轭物：一种新的潜在的吡咯里西啶生物碱DNA反应性代谢产物。
7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids.
作者信息
He Xiaobo, Xia Qingsu, Ma Liang, Fu Peter P
机构信息
a National Center for Toxicological Research, US Food and Drug Administration , Jefferson , Arkansas , USA.
出版信息
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2016;34(1):57-76. doi: 10.1080/10590501.2015.1135593.
Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation.
吡咯里西啶生物碱（PAs）需要代谢活化才能发挥细胞毒性、遗传毒性和致癌性。我们之前报道过，（±）-6,7-二氢-7-羟基-1-羟甲基-5H-吡咯嗪（DHP）衍生的DNA加合物是大鼠体内PA诱导肝肿瘤形成的原因。在本研究中，我们确定，人类或大鼠肝微粒体对阔叶千里光碱和野百合碱的代谢产生了7-半胱氨酸-DHP和DHP。人类和大鼠肝微粒体对7-谷胱甘肽-DHP的代谢也生成了7-半胱氨酸-DHP。此外，7-半胱氨酸-DHP与小牛胸腺DNA在水溶液中的反应产生了上述DHP衍生的DNA加合物。本研究首次报道7-半胱氨酸-DHP是一种可导致DNA加合物形成的新的PA代谢物。
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