Glucuronidation, a New Metabolic Pathway for Pyrrolizidine Alkaloids
Glucuronidation, a New Metabolic Pathway for Pyrrolizidine Alkaloids
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葡萄糖醛酸化，吡咯里西啶生物碱的新代谢途径。
DOI：
10.1021/tx900328f
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发表时间：
2010-03-01
影响因子：
4.1
通讯作者：
Wang, Zheng-Tao
中科院分区：
文献类型：
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作者：
He, Yu-Qi;Yang, Li;Wang, Zheng-Tao
吡咯里西啶生物碱（Pyrrolizidine alkaloids，PAs）经肝脏P450酶代谢活化后对人和动物具有显著的肝毒性。几十年来，人们对PA的代谢途径进行了研究，包括代谢活化、羟基化、N-氧化和水解。然而，完整的PA的葡萄糖醛酸化尚未进行研究，虽然葡萄糖醛酸化在消除和解毒的外源性物质中起着重要的作用。在这项研究中，PAs的葡萄糖醛酸化，并发现了三个要点：首先，我们证明了seneciprimidine（SEN）-一个代表性的肝毒性PA-可以通过尿苷二磷酸葡萄糖醛酸转移酶催化的N-葡萄糖醛酸化反应，在人肝微粒体葡萄糖醛酸结合。第二，SEN的葡萄糖醛酸化不仅被人催化，而且被其他动物物种催化，并且显示出显著的物种差异。兔、牛、羊、猪和人的SEN葡萄糖醛酸化活性显著高于小鼠、大鼠、犬和豚鼠。人、猪和兔的SEN葡萄糖醛酸化动力学遵循Michaelis-Menten方程的单位点结合模型，而牛和羊遵循Michaelis-Menten方程的双位点结合模型。第三，除SEN外，其他肝毒性PA（包括野百合碱、侧金盏花碱和异莲心碱）也在人类和几种动物物种（如兔、牛、羊和猪）中发生N-葡萄糖醛酸化。
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.