Species and Gender Differences Affect the Metabolism of Emodin via Glucuronidation
Species and Gender Differences Affect the Metabolism of Emodin via Glucuronidation
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DOI：
10.1208/s12248-010-9200-6
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发表时间：
2010-09-01
期刊：
影响因子：
4.5
通讯作者：
Liu, Zhongqiu
中科院分区：
文献类型：
--
作者：
Liu, Wei;Tang, Lan;Liu, Zhongqiu
本研究的目的是通过使用肠和肝脏的体外和原位处置模型确定大黄素的代谢来确定大黄素生物利用度差的机制。将小鼠、大鼠、豚鼠、狗和人类的肝微粒体与大鼠肠道灌注模型和大鼠肠微粒体一起使用。在大鼠肠道中，大黄素-3-O-葡萄糖醛酸的排泄率在肠道的四个区域显着不同（p < 0.05），并且雄性高于雌性（p < 0.01）。肝微粒体中的大黄素葡萄糖醛酸化具有物种依赖性，雄性中的K-m值变化5.7倍（3.2-18.2μM），雌性中变化2.8倍（4.6-13.0μM）。男性内在清除率（CLint）值相差5倍（27.6-138.3 mL h(-1)mg(-1)蛋白），女性CLint值相差4.3倍（24.3-103.5 mL h(-1)mg(-1)蛋白）。由于大黄素葡萄糖醛酸化的CLint值比异黄酮高10倍，因此大黄素被认为是快速葡萄糖醛酸化的。与 K-m 和 CLint 值的较大物种依赖性影响相比，性别对这些动力学参数的影响较小（2 倍，p < 0.05）。最后，使用来自相同性别的各种实验动物的肝微粒体获得的葡萄糖醛酸化率与人类肝微粒体中的葡萄糖醛酸化率良好相关。综上所述，UDP-葡萄糖醛酸基转移酶的快速代谢是大黄素生物利用度差的主要原因。物种和性别不同程度地影响大黄素代谢，实验动物有望有助于预测人类大黄素葡萄糖醛酸化。
The aim of the present study was to define the mechanisms responsible for poor bioavailability of emodin by determining its metabolism using in vitro and in situ disposition models of the intestine and liver. Liver microsomes of mice, rats, guinea pigs, dogs, and humans were used along with the rat intestinal perfusion model and the rat intestinal microsomes. In the rat intestine, excretion rates of emodin-3-O-glucuronide were significantly different (p < 0.05) in four regions of the intestine and were higher in males than in females (p < 0.01). Emodin glucuronidation in liver microsomes was species-dependent, and K-m values varied 5.7-fold (3.2-18.2 mu M) in males and 2.8-fold (4.6-13.0 mu M) in females. The male intrinsic clearance (CLint) values differed by 5-fold (27.6-138.3 mL h(-1)mg(-1) protein), and female CLint values differed by 4.3-fold (24.3-103.5 mL h(-1)mg(-1) protein). Since CLint values of emodin glucuronidation were 10-fold higher than that of isoflavones, emodin was considered rapidly glucuronidated. In contrast to the large species-dependent effects on K-m and CLint values, gender had a smaller effect on these kinetic parameters (2-fold, p < 0.05). Lastly, glucuronidation rates obtained using liver microsomes from various experimental animals of the same gender correlated well with those in human liver microsomes. In conclusion, Rapid metabolism by UDP-glucuronosyltransferase is the major reason why emodin has poor bioavailability. Species and gender affected emodin metabolism to a different degree, and experimental animals are expected to be useful in predicting emodin glucuronidation in humans.