Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in dru...Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.展开更多
Background：Orthotopic liver transplantation （OLT） improves the prognosis of patients with hepatocellular carcinoma （HCC）.Moreover,the complement system is a powerful immune effector that can affect liver function...Background：Orthotopic liver transplantation （OLT） improves the prognosis of patients with hepatocellular carcinoma （HCC）.Moreover,the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis.However,studies correlating the complement system with tacrolimus metabolism after OLT are scarce.In this study,the role of single nucleotide polymorphisms （SNPs） associated with the sixth complement component （C6） in tacrolimus metabolism was investigated during the early stages of liver transplantation.Methods：The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013.Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 （CYP3A5） gene were investigated.The tacrolilnus levels were monitored daily during 4 weeks after transplantation.Results：Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose （C/D） ratios.Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios.Recipient CYP3A5 rs776746 allele A （yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2）,C6 rs9200 allele G （exhibited median tacrolimus C/D ratios of 211.31 at week l,110.23 at week 2,and 99.88 at week 3）,and donor CYP3A5 rs776746 allele A （exhibited median C/D ratios of 210.82 at week l,111.06 at week 2,77.49 at week 3,and 85.60 at week 4） and C6 rs 10052999 homozygote （exhibited median C/D ratios of 167.59 at week 2,157.99 at week 3,and 155.36 at week 4） were associated with rapid tacrolimus metabolism.With increasing number of these alleles,patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation.In multiple linear regression analysis,recipient C6 rs9200 group （AA vs.GG/GA） was found to be related to tacrolimus metabolism at weeks 1,2,and 3 （P =0.005,P =0.045,and P =0.033,respectively）,whereas donor C6 rs10052999 group （CC/TT vs.TC） was demonstrated to be correlated with tacrolimus metabolism only at week 4 （P =0.001）.Conclusions：Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.展开更多
Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential ...Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor(PXR)-mediated induction of hepatic cytochrome P4503A4(CYP3A4).The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods:DPX2 cells were used for cell-based PXR reporter assays.The phytochemicals in Gancao extract were identified using a metabolomics approach.The effects of PXR activators identified from in vitro studies were further investigated in PXR-and CYP3A4-humanized mouse models.Results:Gancao was verified to be a PXR-activating herb.Two major phytochemicals in Gancao,gly-cyrrhizin(GZ)and glycyrrhetinic acid(GA),did not activate PXR in the cell-based reporter assays.However,glabridin was shown to activate PXR in a dose-dependent manner.In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator.Although GA did not active PXR in vitro,it induced CYP3A4 expression in a PXR-dependent manner in the PXR-and CYP3A4-humanized mice.展开更多
基金supported,in part,by ALSAC and by the National Institutes of Health grants R35-GM118041 and P30-CA21765.
文摘Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81370579） and the Science and Technology Commission of Shanghai Municipality, China （No. 134119a6300）.
文摘Background：Orthotopic liver transplantation （OLT） improves the prognosis of patients with hepatocellular carcinoma （HCC）.Moreover,the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis.However,studies correlating the complement system with tacrolimus metabolism after OLT are scarce.In this study,the role of single nucleotide polymorphisms （SNPs） associated with the sixth complement component （C6） in tacrolimus metabolism was investigated during the early stages of liver transplantation.Methods：The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013.Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 （CYP3A5） gene were investigated.The tacrolilnus levels were monitored daily during 4 weeks after transplantation.Results：Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose （C/D） ratios.Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios.Recipient CYP3A5 rs776746 allele A （yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2）,C6 rs9200 allele G （exhibited median tacrolimus C/D ratios of 211.31 at week l,110.23 at week 2,and 99.88 at week 3）,and donor CYP3A5 rs776746 allele A （exhibited median C/D ratios of 210.82 at week l,111.06 at week 2,77.49 at week 3,and 85.60 at week 4） and C6 rs 10052999 homozygote （exhibited median C/D ratios of 167.59 at week 2,157.99 at week 3,and 155.36 at week 4） were associated with rapid tacrolimus metabolism.With increasing number of these alleles,patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation.In multiple linear regression analysis,recipient C6 rs9200 group （AA vs.GG/GA） was found to be related to tacrolimus metabolism at weeks 1,2,and 3 （P =0.005,P =0.045,and P =0.033,respectively）,whereas donor C6 rs10052999 group （CC/TT vs.TC） was demonstrated to be correlated with tacrolimus metabolism only at week 4 （P =0.001）.Conclusions：Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.
基金This work was supported by the USA National Center for Com-plementary and Integrative Health Grant R21AT011088(to X.Ma)in part by Grant U54AT008909(to M.F.Paine)+1 种基金in part by the USA National Institute of Allergy and Infectious Diseases Grant R01AI131983(to X.Ma)National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK126875(to X.Ma).
文摘Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor(PXR)-mediated induction of hepatic cytochrome P4503A4(CYP3A4).The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods:DPX2 cells were used for cell-based PXR reporter assays.The phytochemicals in Gancao extract were identified using a metabolomics approach.The effects of PXR activators identified from in vitro studies were further investigated in PXR-and CYP3A4-humanized mouse models.Results:Gancao was verified to be a PXR-activating herb.Two major phytochemicals in Gancao,gly-cyrrhizin(GZ)and glycyrrhetinic acid(GA),did not activate PXR in the cell-based reporter assays.However,glabridin was shown to activate PXR in a dose-dependent manner.In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator.Although GA did not active PXR in vitro,it induced CYP3A4 expression in a PXR-dependent manner in the PXR-and CYP3A4-humanized mice.
