Hepatic and renal metabolism of genistein: An individual-based model to predict glucuronidation behavior of genistein in different organs
The present study aims to develop an individual-based model to predict the glucuronidation characteristics of genistein in 45 human livers. The model was validated in 18 human kidneys. Ten UDP-glucuronosyltransferases (UGTs) were expressed in liver abundantly. Among them, UGT1A1, UGT1A3, UGT1A6, UGT1A9 and UGT2B7 contributed 95.6% to genistein glucuronidation in human liver, with significant correlation between gene expression of the five UGTs and the glucuronidation of genistein. The genistein glucuronidation differences between individuals were varied enormously; meanwhile the expression variations can explain 24.7% total metabolic variation in livers. In kidney, UGT1A6, UGT1A9 and UGT2B7 were amply expressed. Their gene expressions and glucuronidation rates of genistein had high correlations. Expression variations of UGT1A9/2B7 can explain up to 40.9% of the total variation of genistein glucuronidation in kidney. The model was therefore established based on UGT expression between individuals taking into account an important assessment which is the ratio of metabolic rate of each recombinant UGT isoform. Excellent linear correlations between predicted and observed glucuronidation rate revealed that the model could predict metabolic activity of genistein using quite a small size of tissue. In conclusion, the individual-based model can be employed for predicting individual glucuronidation behavior of genistein in different organs.