Disposition of flavonoids via enteric recycling: UDP-glucuronosyltransferase (UGT) 1As deficiency in Gunn rats is compensated by increases in UGT2Bs activities.
Flavonoids have poor bioavailabilities largely because of metabolism via UDP-glucuronosyltransferases (UGTs). This study aims to further understand the functions of UGT in metabolizing genistein and apigenin, two compounds metabolized more extensively in the gut than in the liver. Because Gunn rats are deficient in UGT1As, we determined whether this deficiency would result in less flavonoid glucuronidation, using rat intestinal perfusion model and microsomes prepared from rat liver and intestine. In yeast-expressed rat UGT isoforms, rat UGT1A isoforms (especially UGT1A7) were mainly responsible for flavonoid metabolism. In perfusion studies, the two flavonoids were rapidly absorbed at comparable rates, but the intestinal excretions of glucuronides in Gunn rats compared with Wistar rats were not only comparable for genistein but also were higher (p < 0.05) for apigenin, suggesting up-regulation of UGT isoforms in Gunn rats. To determine the possible compensatory UGT isoforms, we first verified that UGT1A activities were significantly lower (p < 0.05) in Gunn rats by using UGT1A-specific probes 7-ethyl-10-hydroxycamptothecin (SN-38) and prunetin. We then demonstrated using UGT2B probes testosterone, ezetimibe, and indomethacin that UGT2B activities were usually significantly higher in Gunn rats. In addition, testosterone was metabolized much faster in liver microsomes than in intestinal microsomes, and in microsomes prepared from Gunn rats compared with Wistar rats. In conclusion, flavonoids are efficiently metabolized by UGT1A-deficient Gunn rats because of compensatory up-regulation of intestinal UGT2Bs and hepatic anion efflux transporters, which increases their disposition and limits their oral bioavailabilities.
Wang
Stephen W J
SW
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund St., University of Houston, Houston, TX 77204, USA.
Kulkarni
Kaustubh H
KH
Tang
Lan
L
Wang
Jing Rong
JR
Yin
Taijun
T
Daidoji
Tomo
T
Yokota
Hiroshi
H
Hu
Ming
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism; D047310:Apigenin / Q000378:metabolism; D001384:Azetidines / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D000069438:Ezetimibe; D005419:Flavonoids / Q000378:metabolism*; D019833:Genistein / Q000378:metabolism; D020723:Glucuronic Acid / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007213:Indomethacin / Q000378:metabolism; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D000077146:Irinotecan; D007529:Isoflavones / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism*; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D000924:Anticholesteremic Agents; D001384:Azetidines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007529:Isoflavones; D020033:Protein Isoforms; D011994:Recombinant Proteins; C083295:prunetin; D013739:Testosterone; D000077146:Irinotecan; D047310:Apigenin; D020723:Glucuronic Acid; D019833:Genistein; D014453:Glucuronosyltransferase; D000069438:Ezetimibe; D002166:Camptothecin; D007213:Indomethacin