Disposition of flavonoids via enteric recycling: enzyme-transporter coupling affects metabolism of biochanin A and formononetin and excretion of their phase II conjugates.
The purpose of this study was to continue our effort to determine how enzyme-transporter coupling affect disposition of flavonoids. The rat intestinal perfusion and Caco-2 cell models were used together with relevant microsomes. In perfusion model, isoflavone (i.e., formononetin and biochanin A) absorption and subsequent excretion of its metabolites were always site-dependent. Maximal amounts of intestinal and biliary conjugates excreted per 30 min were 31 and 51 nmol for formononetin, more than that for pure biochanin A (12 and 20 nmol). When a standardized red clover extract (biochanin A/formononetin = 10:7) was used, the results indicated that more metabolites of biochanin A than formononetin were found in the perfusate (36.9 versus 22.8 nmol) and bile (78 versus 51 nmol). In metabolism studies, rat intestinal and liver microsomes always glucuronidated biochanin A faster (p < 0.05) than formononetin, whereas intestinal microsomes glucuronidated both isoflavones faster (p < 0.05) than liver microsomes. However, rapid metabolism in the microsomes did not translate into more efficient excretion in either the rat perfusion model as shown previously or in the Caco-2 model. In the Caco-2 model, both isoflavones were rapidly absorbed, efficiently conjugated, and the conjugates excreted apically and basolaterally. More formononetin conjugates were excreted than biochanin A when used alone, but much more biochanin A conjugates were found when using the isoflavone mixture. In conclusion, efficiency of enzyme-transporter coupling controls the amounts of metabolites excreted by the intestine and liver and determines the relative contribution of enteric and enterohepatic recycling to the in vivo disposition of isoflavones.
Jia
Xiaobin
X
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6510, USA.
Chen
Jun
J
Lin
Huimin
H
Hu
Ming
M
D000042:Absorption; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells; D019833:Genistein / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007529:Isoflavones / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D007700:Kinetics; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D029921:Trifolium / Q000737:chemistry
D020719:Glucuronides; D007529:Isoflavones; D026901:Membrane Transport Proteins; C007768:formononetin; D019833:Genistein; C004541:biochanin A