Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes an...Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.展开更多
UDP-glucuronosyltransferase 1A9(UGT1A9) is a major phase II enzyme responsible for elimination of drugs and endogenous molecules.Clinical data have shown increased elimination of UGT1A9 substrates in pregnant women or...UDP-glucuronosyltransferase 1A9(UGT1A9) is a major phase II enzyme responsible for elimination of drugs and endogenous molecules.Clinical data have shown increased elimination of UGT1A9 substrates in pregnant women or oral contraceptive users,but the role of estrogen in the regulation of UGT1A9 expression remains unknown.In this study,we investigated the effect of 17β-estradiol(E2) on UGT1A9 expression and the role of ERα in the transcriptional regulation of UGT1A9.E2 significantly increased UGT1A9 promoter activity in Hep G2 cells in the presence of ERα.UGT1A9 induction by E2 was abrogated by antiestrogen ICI182,780 in Hep G2 cells that constitutively express ERα.Results from transient transfection of ERα mutants into Hep G2 cells demonstrated that mutation at DNA-binding domain of ERα abrogates increased UGT1A9 promoter activity by E2.Deletion and mutation assays of UGT1A9 promoter revealed a putative ERE located within -2262/-1987 region.Examination of healthy human liver tissues revealed significantly higher UGT1A9 expression in women as compared to men.Together,these findings provide a mechanistic basis for the previous clinical reports and may shed a light on identifying sources for inter-individual variability in UGT1A9-mediated drug metabolism.展开更多
基金supported by grants of U01CA175315 and R01GM113888 from the U.S.National Institutes of Health(NIH)supported by grants of ES006694 and ES007091 from NIH+8 种基金supported by grants of ES021800,ES020522,and ES005022 from NIHsupported by the Robert Bosch Foundation,Stuttgart,Germanysupported by grants of ES023438 and DK083952 from NIHsupported by grant of R01HL122593 from NIH and the Searle Scholars Program,USAsupported by grant of R01ES025708 from NIHsupported by grants of CA098468 and T32DK007737 from NIHsupported by grants of R01DK33765 and R01ES024421 from NIHsupported by grants of R01DK104656,R01DK080440,R01ES025909,R21AA022482,and R21AA024935 from NIH,grant of 1I01BX002634 from VA Merit Award,USA,grant of No.81572443 from National Natural Science Foundation of China,and grant of P30 DK34989 from Yale Liver Center,USAsupported by grants of R01ES019487,R01GM087367,and R01GM118367 from NIH
文摘Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.
基金supported by the U.S. National Institute of Health (Grants HD065532 and GM112746)
文摘UDP-glucuronosyltransferase 1A9(UGT1A9) is a major phase II enzyme responsible for elimination of drugs and endogenous molecules.Clinical data have shown increased elimination of UGT1A9 substrates in pregnant women or oral contraceptive users,but the role of estrogen in the regulation of UGT1A9 expression remains unknown.In this study,we investigated the effect of 17β-estradiol(E2) on UGT1A9 expression and the role of ERα in the transcriptional regulation of UGT1A9.E2 significantly increased UGT1A9 promoter activity in Hep G2 cells in the presence of ERα.UGT1A9 induction by E2 was abrogated by antiestrogen ICI182,780 in Hep G2 cells that constitutively express ERα.Results from transient transfection of ERα mutants into Hep G2 cells demonstrated that mutation at DNA-binding domain of ERα abrogates increased UGT1A9 promoter activity by E2.Deletion and mutation assays of UGT1A9 promoter revealed a putative ERE located within -2262/-1987 region.Examination of healthy human liver tissues revealed significantly higher UGT1A9 expression in women as compared to men.Together,these findings provide a mechanistic basis for the previous clinical reports and may shed a light on identifying sources for inter-individual variability in UGT1A9-mediated drug metabolism.
