Species and Gender Differences Affect the Metabolism of Emodin via Glucuronidation
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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 μM) in males and 2.8-fold (4.6–13.0 μM) 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.
Key wordsemodin glucuronidation first-pass metabolism gender species UGT
This work was mainly supported by Key Project of Chinese National Programs for Fundamental Research and Development (973 program) 2009CB522800, and the Grant of Science and Technology of Guangzhou 2006Z1-E6021, both to ZL. MH was also supported by NIH GM070737.
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