Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression a...Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression and activity of many inflammatory cytokines are markedly affected.Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes(DMEs).Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs.Xenobiotic receptors in turn may affect the clinical outcomes of sepsis.Thisreview focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor(PXR),aryl hydrocarbon receptor(AHR),glucocorticoid receptor(GR),and constitutive androstane receptor(CAR),DMEs such as CYP1A,CYP2B6,CYP2C9,and CYP3A4,and drug transporters such as p-glycoprotein(P-gp),and multidrug resistance-associated protein(MRPs)that are affected by sepsis.Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.展开更多
AIM: To study the effect of Buyang Huanwu Decoction(BYHWD) on the antioxidant enzymes and drug-metabolizing enzymes in rat liver. METHOD: Following treatment of rats with BYHWD at 6.42, 12.83, or 25.66 g·kg–1 pe...AIM: To study the effect of Buyang Huanwu Decoction(BYHWD) on the antioxidant enzymes and drug-metabolizing enzymes in rat liver. METHOD: Following treatment of rats with BYHWD at 6.42, 12.83, or 25.66 g·kg–1 per day for 15 days, microsomes and cytosols isolated from the liver tissues were prepared by differential centrifugation according to standard procedures. The activities of the antioxidant enzymes and cytochrome b5, NADPH-cytochrome P450 reductase, CYP3 A, CYP2E1, UGT, and GST of the rat livers were determined by UV-Vis spectrophotometer. RESULTS: The activities of ALT, AST, antioxidant enzymes, and the Hepatosomatic Index in serum were not significantly affected. In cytosols, the activity of CAT was significantly increased at the dosage of 12.83 g·kg–1, and all the other antioxidant activities and MDA levels were not affected by this treatment. BYHWD had no effect on cytochrome b5, NADPH-cytochrome P450 reductase, CYP3 A, and UGT. At the highest dose(25.66 g·kg–1), the activity of CYP2E1 was significantly inhibited, and the activities of GST and the level of GSH were increased. CONCLUSION: BYHWD is safe for the liver, and has the functions of detoxification and antioxidant. Patients should be cautioned about the herb-drug interaction of BYHWD and CYP2E1 substrates.展开更多
Intestine is responsible for the biotransformation of many orally-exposed chemicals.The constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters...Intestine is responsible for the biotransformation of many orally-exposed chemicals.The constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters(drug-processing genes/DPGs) in liver,but less is known regarding its effect in intestine.Sixty-day-old wild-type and Car / mice were administered the CARligand TCPOBOP or vehicle once daily for 4 days.In wild-type mice,Car m RNA was down-regulated by TCPOBOP in liver and duodenum.Car / mice had altered basal intestinal expression of many DPGs in a section-specific manner.Consistent with the liver data(Aleksunes and Klaassen,2012),TCPOBOP upregulated many DPGs(Cyp2b10,Cyp3a11,Aldh1a1,Aldh1a7,Gsta1,Gsta4,Gstm1-m4,Gstt1,Ugt1a1,Ugt2b34,Ugt2b36,and Mrp2–4) in specific sections of small intestine in a CAR-dependent manner.However,the m RNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine.Interestingly,many known CAR-target genes were highest expressed in colon where CAR is minimally expressed,suggesting that additional regulators are involved in regulating their expression.In conclusion,CAR regulates the basal expression of many DPGs in intestine,and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine,pharmacological activation of CAR in liver and intestine are not identical.展开更多
Polymorphisms associated with genes coding for a variety of drug-metabolizing enzymes （DMEs） and associated transport proteins can influence the drug metabolism rate of individuals, potentially affecting the efficac...Polymorphisms associated with genes coding for a variety of drug-metabolizing enzymes （DMEs） and associated transport proteins can influence the drug metabolism rate of individuals, potentially affecting the efficacy of drug and the occurrence of adverse reactions. Single nucleotide polymorphisms （SNPs） are prevalent in all types of genetic variations. Reliable SNP genotyping provides excellent markers for detecting genetic polymolphisms, genetic disorders, and resistance of pathogen to drug, which are needed for the genetic diagnosis of disease and subtle genetic factors. With a large number of SNP genotyping studies being conducted, a lot of novel SNP identifying methods have been developed. Several SNP genotyping methods and techniques have been introduced for clinical test. These include TaqMan drug metabolism genotyping assays, pH-sensing semiconductor system, high-resolution melting curve analysis （HRM） of polymerase chain reaction （PCR） amplicons, novel multiplexed electrochemical biosensor with non-fouling surface, DNA hybridization detection using less than 10-nm gap silicon nanogap structure, tetra-primer ARMS-PCR method, acoustic detection of DNA conformation in genetic assays combined with PCR, microbeads-mass spectrometry （MEMS）-based approach, and liquid chromatography-electrospray ionization mass spectrometry. Personalized medicine has changed the conventional ways of using drugs according to experiences. It focuses on making the individualized pattern for each individual based on their own characteristics. Lots of researchers are using the analysis of clinical samples to explain the relationship between the drug adverse reactions and genetic polymorphisms. But it takes a long time from collecting the blood samples for DNA extraction and genotyping to getting results on the side effect of drug through clinical study. Therefore, it is desirable to develop improved in vitro methods to study the drug metabolizing-enzymes and transport protein genetic polymorphisms.展开更多
基金the Engineering Project for Innovative Scholars of He-nan Province(2004107014).This work was carried out in He-nan Key Laboratory for Molecular Medicine.
基金supported by grants from the National Natural Science Foundation of China(8140130969and 8176130232)Hainan Provincial Science and Technology Major Project(ZDKJ201804,China).
文摘Sepsis is an infection-induced systemic inflammatory syndrome.The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways.When sepsis occurs,the expression and activity of many inflammatory cytokines are markedly affected.Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes(DMEs).Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs.Xenobiotic receptors in turn may affect the clinical outcomes of sepsis.Thisreview focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor(PXR),aryl hydrocarbon receptor(AHR),glucocorticoid receptor(GR),and constitutive androstane receptor(CAR),DMEs such as CYP1A,CYP2B6,CYP2C9,and CYP3A4,and drug transporters such as p-glycoprotein(P-gp),and multidrug resistance-associated protein(MRPs)that are affected by sepsis.Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis.
基金supported by the National Natural Science Foundation of China(No.81060353)Program for New Century Excellent Talent in University(NCET)of China from Ministry of Education of China(Doc.2010-14,NCET-10-0093)Natural Science Foundation of Guangxi province of China(No.2011GXNSFF018006)
文摘AIM: To study the effect of Buyang Huanwu Decoction(BYHWD) on the antioxidant enzymes and drug-metabolizing enzymes in rat liver. METHOD: Following treatment of rats with BYHWD at 6.42, 12.83, or 25.66 g·kg–1 per day for 15 days, microsomes and cytosols isolated from the liver tissues were prepared by differential centrifugation according to standard procedures. The activities of the antioxidant enzymes and cytochrome b5, NADPH-cytochrome P450 reductase, CYP3 A, CYP2E1, UGT, and GST of the rat livers were determined by UV-Vis spectrophotometer. RESULTS: The activities of ALT, AST, antioxidant enzymes, and the Hepatosomatic Index in serum were not significantly affected. In cytosols, the activity of CAT was significantly increased at the dosage of 12.83 g·kg–1, and all the other antioxidant activities and MDA levels were not affected by this treatment. BYHWD had no effect on cytochrome b5, NADPH-cytochrome P450 reductase, CYP3 A, and UGT. At the highest dose(25.66 g·kg–1), the activity of CYP2E1 was significantly inhibited, and the activities of GST and the level of GSH were increased. CONCLUSION: BYHWD is safe for the liver, and has the functions of detoxification and antioxidant. Patients should be cautioned about the herb-drug interaction of BYHWD and CYP2E1 substrates.
基金supported by grants from the National Science and Technology Major Project (No. 2008ZXJ09014-010)the National Natural Science Foundation of China (No. 81401552+6 种基金 81403004 and 81673508)Major Program of the "Twelfth Five-year Plan" for Logistic Science of PLA (No. AWS14L0005)Major Program of the "Twelfth Five-year Plan" for Medical Science of PLA (No. BWS12J012)the Natural Science Foundation of Gansu Province China (No. 145RJZA111 1606RJZA176)
基金supported by U.S. National Institute of Health R-01 grants ES019487,ES025708,and GM11138start-up funds from University of Washington Center for Ecogenetics and Environmental Health (P30ES007033)
文摘Intestine is responsible for the biotransformation of many orally-exposed chemicals.The constitutive androstane receptor(CAR/Nr1i3) is known to up-regulate many genes encoding drugmetabolizing enzymes and transporters(drug-processing genes/DPGs) in liver,but less is known regarding its effect in intestine.Sixty-day-old wild-type and Car / mice were administered the CARligand TCPOBOP or vehicle once daily for 4 days.In wild-type mice,Car m RNA was down-regulated by TCPOBOP in liver and duodenum.Car / mice had altered basal intestinal expression of many DPGs in a section-specific manner.Consistent with the liver data(Aleksunes and Klaassen,2012),TCPOBOP upregulated many DPGs(Cyp2b10,Cyp3a11,Aldh1a1,Aldh1a7,Gsta1,Gsta4,Gstm1-m4,Gstt1,Ugt1a1,Ugt2b34,Ugt2b36,and Mrp2–4) in specific sections of small intestine in a CAR-dependent manner.However,the m RNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine.Interestingly,many known CAR-target genes were highest expressed in colon where CAR is minimally expressed,suggesting that additional regulators are involved in regulating their expression.In conclusion,CAR regulates the basal expression of many DPGs in intestine,and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine,pharmacological activation of CAR in liver and intestine are not identical.
基金The Influence of Artesunate on β-catenin Signaling Pathway of Hetatic Atellate Cells(Grant No.2011CDB491)
文摘Polymorphisms associated with genes coding for a variety of drug-metabolizing enzymes （DMEs） and associated transport proteins can influence the drug metabolism rate of individuals, potentially affecting the efficacy of drug and the occurrence of adverse reactions. Single nucleotide polymorphisms （SNPs） are prevalent in all types of genetic variations. Reliable SNP genotyping provides excellent markers for detecting genetic polymolphisms, genetic disorders, and resistance of pathogen to drug, which are needed for the genetic diagnosis of disease and subtle genetic factors. With a large number of SNP genotyping studies being conducted, a lot of novel SNP identifying methods have been developed. Several SNP genotyping methods and techniques have been introduced for clinical test. These include TaqMan drug metabolism genotyping assays, pH-sensing semiconductor system, high-resolution melting curve analysis （HRM） of polymerase chain reaction （PCR） amplicons, novel multiplexed electrochemical biosensor with non-fouling surface, DNA hybridization detection using less than 10-nm gap silicon nanogap structure, tetra-primer ARMS-PCR method, acoustic detection of DNA conformation in genetic assays combined with PCR, microbeads-mass spectrometry （MEMS）-based approach, and liquid chromatography-electrospray ionization mass spectrometry. Personalized medicine has changed the conventional ways of using drugs according to experiences. It focuses on making the individualized pattern for each individual based on their own characteristics. Lots of researchers are using the analysis of clinical samples to explain the relationship between the drug adverse reactions and genetic polymorphisms. But it takes a long time from collecting the blood samples for DNA extraction and genotyping to getting results on the side effect of drug through clinical study. Therefore, it is desirable to develop improved in vitro methods to study the drug metabolizing-enzymes and transport protein genetic polymorphisms.
