Species and Gender Differences Affect the Metabolism of Baicalein via Glucuronidation
Baicalein (5,6,7-trihydroxyflavone) is one of the typical representatives of flavonoids, which isolated from Scutellaria baicalensis Georgi, and has been demonstrated to possess a variety of biological activities, including treatment of inflammation, cardiovascular disease and microbial infections.Recently,accumulating evidence has been demonstrated the antitumor activity of this flavone in a variety of human cancer cell lines in vitro.Though it has so many pharmacological effects, its species diversity remains unclear.The aim of this study was to define the mechanisms responsible for poor bioavailability of Baicalein by its metabolism using in vitro of liver.Liver microsomes of Rhesus monkeys, SD rats, Beagle dogs, pigs and humans, among which Rhesus monkeys, SD rats and Beagle dogs using gender comparison, were employed to phase Ⅱ metabolic incubation system.Origin8.0 software was used for Analysis of kinetic data and evidenced by a liner Eadie-Hofstee plot.Our experiment revealed that there are three glucuronidation metabolites of Baicalein incubated with human liver microsomes, monkey liver microsomes, SD rats(F/M) liver microsomes, dog(F/M) liver microsomes and pig microsomes at 37℃ for 30min and determined by using of HPLCUV.Through the analysis of kinetic data, the Km values of Baicalein-7-glucuronidation in human liver microsomes (Km=1.74) was about 25-fold lower than in female SD rats (Km=43.8).The metabolite Baicalein-6-glucuronidation was catalyzed by liver microsomes, which is an active metabolite with 16-fold higher affinity to the SD rats (Km=0.56) than Rhesus monkeys (Km=9.39).The other metabolite,Baicalein-6-O-glucuronidation-7-O-glucuronidation, in native hepatic microsomes from female SD rats (Km=156) liver displayed higher Km values than that in pigs(Km=6.48).In human liver microsomes, metabolites of Ba, BG” and BGG, Km values were 3.93 and 88.4, respectively.Results suggest that we should not select single animal model to conduct animal experiment.Besides, our data also showed that there is a great difference in gender in some species, BG, BG” and BGG in SD rats and BG in dogs having remarkable differences.The species and gender metabolic differences we observed between animals and human liver provide key information for delineating Baicalein pharmacokinetics needed for human health risk assessment.In conclusion, species and gender affected Baicalein metabolism to a different degree, and experimental animals are expected to be useful predicting Baicalein glucuronidation in humans.
Baicalein Metabolism Glucuronidation UDP-glucuronosyltransferase Enzyme Kinetics
Wu Yuan Dong Ruihua Liu Zeyuan
Department of Clinical Pharmacology, Affiliated Hospital, Academy of Military Medical Sciences.Beijing, 100071, China
国内会议
长沙
英文
10-19
2013-06-06（万方平台首次上网日期，不代表论文的发表时间）