Salvianolic acid B modulates the expression of drug-metabolizing enzymes in HepG2 cells

BACKGROUND: Enzymes involved in drug and xenobiotic metabolism have been considered to exist in two groups: phase I and phase II enzymes. Cytochrome P450 isoenzymes (CYPs) are the most important phase I enzymes in the metabolism of xenobiotics. The products of phase I metabolism are then acted upon by phase II enzymes, including glutathione S-transferases (GSTs). Herbs that inhibit CYPs such as CYP3A4 or that induce GSTs may have the potential to protect against chemical carcinogenesis since the mutagenic effects of carcinogens are often mediated through an excess of CYP-generated reactive intermediates. This study was designed to investigate the effects of salvianolic acid B (Sal B), a pure compound extracted from Radix Salviae Miltiorrhizae, a Chinese herb, on cell proliferation and CYP1A2 and CYP3A4 mRNA expression in the presence or absence of rifampicin, a potent inducer of CYPs and GST protein expression in HepG2 cells. METHODS: HepG2 cells were incubated with different concentrations of Sal B. Cell proliferation was determined by SYTOX-Green nucleic acid staining. CYP3A4 and CYP1A2 mRNA expression was assayed by real-time PCR. GST protein expression was analyzed by Western blotting. RESULTS: Low concentrations of Sal B (0-20 μmol/L) had no significant effects on cell proliferation, while higher concentrations (100-250 μmol/L) significantly inhibited proliferation in a concentration-dependent manner. Ten μmol/L Sal B, but not 1 μmol/L, down-regulated CYP3A4 and CYP1A2 mRNA expression after 24 hours of incubation, whereas both 1 and 10 μmol/L Sal B down-regulated CYP3A4mRNA expression after 96 hours of incubation; moreover, 1 and 10 μmol/L Sal B inhibited CYP3A4 mRNA expression induced by rifampicin. Both 1 μmol/L and 10 μmol/L Sal B increased GST expression. CONCLUSION: Sal B inhibits CYP3A4 and CYP1A2 mRNA expression and induces GST expression in HepG2 cells.

Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in HepG2 spheroids

Three-dimensional(3D)cell spheroid models combined with mass spectrometry imaging(MSI)enables innovative investigation of in vivo-like biological processes under different physiological and pathological conditions.Herein,airflow-assisted desorption electrospray ionization-MSI(AFADESI-MSI)was coupled with 3D HepG2 spheroids to assess the metabolism and hepatotoxicity of amiodarone(AMI).High-coverage imaging of>1100 endogenous metabolites in hepatocyte spheroids was achieved using AFADESI-MSI.Following AMI treatment at different times,15 metabolites of AMI involved in Ndesethylation,hydroxylation,deiodination,and desaturation metabolic reactions were identified,and according to their spatiotemporal dynamics features,the metabolic pathways of AMI were proposed.Subsequently,the temporal and spatial changes in metabolic disturbance within spheroids caused by drug exposure were obtained via metabolomic analysis.The main dysregulated metabolic pathways included arachidonic acid and glycerophospholipid metabolism,providing considerable evidence for the mechanism of AMI hepatotoxicity.In addition,a biomarker group of eight fatty acids was selected that provided improved indication of cell viability and could characterize the hepatotoxicity of AMI.The combination of AFADESI-MSI and HepG2 spheroids can simultaneously obtain spatiotemporal information for drugs,drug metabolites,and endogenous metabolites after AMI treatment,providing an effective tool for in vitro drug hepatotoxicity evaluation.

Drosophila melanogaster as an indispensable model to decipher the mode of action of neurotoxic compounds

Exposure to some toxic compounds causes structural and behavioral anomalies associated with the neurons in the later stage of life.Those toxic compounds are termed as a neurotoxicant,which can be a physical factor,a toxin,an infection,radiation,or maybe a drug.The incongruities caused due to a neurotoxicant further depend on the toxicity of the compound.More importantly,the neurotoxicity of the compound is associated with the concentration and the time point of exposure.The neurodevelopmental defect appears depending on the toxicity of the compound.A neurodevelopmental defect may be associated with a delay in developmental time,defective growth,structural abnormality of many organs,including sensory organs,behavioral abnormalities,or death in the fetus stage.Numerous model organisms are employed to assess the effect of neurotoxicants.The current review summarizes several methods used to check the effect of neurotoxicant and their effect using the model organism Drosophila melanogaster.

Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells

Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors.Herein,we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry(sDMH-scMS)by integrating living-cell electrolaunching ionization MS(ILCEI-MS)and high-performance liquid chromatography-MS(HPLC-MS)analysis,and the primary resistance of NSCLC cells to gefitinib was studied using this platform.The ILCEI-MS analysis showed that approximately 11.9%of NSCLC single cells contained the gefitinib metabolite M11;HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells.The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells,and the intensity of gefitinib metabolites was significantly higher than in PC9 cells,suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism.Moreover,the combination of gefitinib and the drug-metabolizing enzyme inhibitorα-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells.Overall,the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.

Phenotype prediction of nonsynonymous single nucleotide polymorphisms in human phase II drug/xenobiotic metabolizing enzymes: perspectives on molecular evolution

Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.

pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P < 0.01). At variance, m RNA and protein expression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.

Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology

BACKGROUND The coronavirus disease 2019(COVID-19),a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide,was described to be frequently accompanied by extrapulmonary manifestations,including liver dysfunction.Liver dysfunction and elevated liver enzymes were observed in about 53%of COVID-19 patients.AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed.Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways.The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis,fibrosis,non-alcoholic fatty liver disease(NAFLD),and hepatitis A/B/C.Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes,DNAJB1,IGF2,EGFR,and HDGF.Concordantly,the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling(liver cirrhosis,Fibrosis,NAFLD,and hepatitis A/B/C).Moreover,we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function,including cytochrome P450 family members,ACAD11,CIDEB,GNMT,and GPAM.Consequently,drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity.In correspondence with the RNA-seq data analysis,we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling,mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.

Screening of the whole human cytochrome P450 complement(CYPome)with enzyme bag cocktails

We have previously introduced the use of permeabilized fission yeast cells(enzyme bags)that recombinantly express full-length CYPs for drug metabolism studies.Such enzyme bags are cells with pores that function as enzymes in situ.They can easily be prepared without a need for ultracentrifugation and may be used in similar protocols as microsomes.In this study we report the preparation of enzyme bag cocktails that permit the testing of multiple CYPs in a single enzyme bag reaction.Moreover,we established a convenient testing scheme that permits a rapid screen of all human CYPs for activity towards any given candidate substrate.An important aspect of this approach is the reduction of individual CYP test assays.If a cocktail containing many CYPs tests negative,it follows that all CYPs included in that cocktail need not be tested individually,thus saving time and resources.The new protocol was validated using two probe substrates.

Voriconazole-Induced Periostitis &Enthesopathy in Solid Organ Transplant Patients: Case Reports

Background: Voriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis. Aim: Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. Case Presentation: Voriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes. Conclusions: Voriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase and fluoride levels, voriconazole trough and bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes.

Generation and characterization of a novel CYP3A1/2 double knockout rat model using CRISPR-Cas9 system

OBJECTIVE Cytochrome P450(CYP)3A accounts for nearly 30%of total CYP enzymes in human liver and participates in the metabolism of over 50%of clinical drugs.CYP3A also plays an important role in the chemical metabolism,toxicity,and carcinogenicity.New animal models are needed to investigate CYP3A functions.METHODS The CRISPR-Cas9 technology was used to generate Cyp3a1/2 double knockout rat model.The absence of Cyp3a1/2 expression was evaluated through PCR and immunostaining.Metabolic studies of the CYP3A substrates midazolam and nifedipine both in vitro and in vivo were conducted to verify that CYP3A1/2 was functional y inactive in KO rats.In addition,compensatory up-regulation of other P450 genes in Cyp3a1/2 KO rats was detected.RESULTS The Cyp3a1/2 double KO rats were viable and fertile,and had no obvious physiological abnormities.Compared with the wild-type(WT)rat,Cyp3a1/2 expression was completely absent in the liver of the KO rat.In vitro and in vivo metabolic studies of the CYP3A1/2 substrates indicated that CYP3A1/2 was functionally inactive in double KO rats.CONCLUSION The Cyp3a1/2 double KO rat model was successfully generated and characterized.The Cyp3a1/2 KO rats as a novel rodent animal model will be a valuable tool for the study of the physiological and pharmacological roles of CYP3A,and determining whether the absence of CYP3A results in non-CYP mediated metabolism or metabolism by other CYP isoforms.

Microdosing cocktail study on the determination and pharmacokinetics of six hepatic cytochrome probes and their metabolites in rat

OBJECTIVE To describe a highly sensitive LC-ESI MSnmethod that was developed to simultaneously detect six CYP isoform-specific probes and their metabolites in rat plasma for microdosing cocktail study.METHODS After administration of a mixture of six probes(i.e.,a cocktail approach with caffeine 100μg·kg-1,tolbutamide100μg·kg-1,omeprazole 500μg·kg-1,dextromethorphan 500μg·kg-1,chlorzoxazone 50μg·kg-1and midazolam 100μg·kg-1)to SD rats.The plasma samples were extracted using ethyl acetate with diazepam and gliclazide as the IS.The assay was performed on an Agilent Eclipse Plus C18 column(2.1×50 mm,3.5μm).The mobile phase consisted of 0.01%formic acid(1 mmol·L-1ammonium formate)and acetonitrile.The flow rate was0.3 m L·min-1.The samples were analyzed by LC-20A&5500Qtrap ESI MSnin MRM mode.The MS/MS reaction selected 181.2/124.0 m/z ions for caffeine,195.2/138.2m/z for paraxanthine,269.1/170.0 m/z for tolbutamide,285.1/186.0 m/z for 4-hydroxytolbutamide,346.1/198.1m/z for omeprazole,362.2/214.2 m/z for 5-hydroxyomeprazole,272.3/147.1 m/z for dextromethorphan,258.2/157.0 m/z for dextrorphan,168.1/132.1 m/z for chlorzoxazone,326.1/291.2 m/z for midazolam,and 342.1/324.2m/z for 1′-hydroxymidazolam.RESULTS The datashowed that the method was with good linearity in the range of 0.2-200 ng·m L-1for caffeine,0.1-25 ng·m L-1for paraxanthine,0.05-100 ng·m L-1for omeprazole,0.01-25 ng·mL-1for 5-hydroxyomeprazole,0.1-200 ng·mL-1for dextromethorphan,0.05-12.5 ng·mL-1for dextrophan,0.2-200 ng·mL-1for midazolam,and 0.2-25 ng·mL-1for 1′-hydroxymidazolam,respectively.The stability%RSD for al probes was less than 15%and matrix effects in plasma on the ionization were negligible.CONCLUSION This highly sensitive and quantitative method allowed a pharmacokinetic study in subjects receiving doses 10-100 times lower than typical therapeutic doses.The established LCMS/MS method was suitable for pharmacokinetic study of this mixture cocktail probe group and could be applied deeply to CYP isoforms(1A2,2C9,2C19,2D6,2E1and 3A)research.

Antiparasitic Sesquiterpenes from the Cameroonian Spice Scleria striatinux and Preliminary In Vitro and In Silico DMPK Assessment

We are grateful for financial support from the International Cooperative Biodiversity Groups(ICBG),a program of the Fogarty International Centre of the National Institutes of Health(NIH),USA through grant(no TW00327)awarded to Professor S.M.N.Efange and Medicines for Malaria Venture(MMV),Geneva,Switzerland.The US Fulbright Council for International Exchange of Scholars(CIES)is acknowledged for grant to Kennedy D.Nyongbela to carry-out research at the University of Minnesota.We wish to thank M.Campbell and A.Powell from the Centre for Drug Candidate Optimisation(CDCO),Monash University for the DMPK data.Fidele Ntie-Kang is currently a Georg Forster fellow of the Alexander von Humboldt Foundation,Germany.We are equally grateful to Schro¨dinger Inc.for the academic license to use the QikProp software.

Microbial-host-isozyme:a new territory for understanding personalized responses towards drug therapy

Inter-individual responses to medicinal drugs vary widely in clinic,which drives the urgent need of precision medicine for minimizing adverse reactions and maximalizing therapeutic effects among patients[1].In addition to genetic factors,increasing evidence suggests that gut microbiome plays a crucial role in affecting either pharmacodynamics or pharmacokinetics[2].In recent years,at least two ways have been demonstrated through which gut microbiome jointly affects drug metabolism or efficacy with host.One is the microbial metabolism on drugs.Zimmermann et al.[3]systematically studied the direct interaction between microorganisms and drugs.They found that 2/3 of the 271 selected orally administered drugs could be metabolized by at least one strain.They also verified that 30 enzymes encoded by microorganisms have the ability to transform 20 drugs into 59 candidate metabolites.The direct interaction between gut microbiota and drugs,including chemical modification(such as sulfasalazine[4]),inactivation(such as digoxin[5])or changes in toxicity(such as irinotecan[6]).Another way is the bioaccumulation of drugs in gut bacteria that alters drug availability and metabolism.Klünemann et al.[7]investigated the depletion of 15 drugs with different structures by 25 representative strains.This study reveals 70 interactions between bacteria and drugs,of which 29 have not been reported in previous studies,and more than half of the new interactions can be attributed to bioaccumulation.

Epigenetic regulation of drug metabolism and transport

The drug metabolism is a biochemical process on modification of pharmaceutical substances through specialized enzymatic systems. Changes in the expression of drug-metabolizing enzyme genes can affect drug metabolism. Recently, epigenetic regulation of drug-metabolizing enzyme genes has emerged as an important mechanism. Epigenetic regulation refers to heritable factors of genomic modifications that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, and non-coding RNAs. This review examines the widespread effect of epigenetic regulations on genes involved in drug metabolism, and also suggests a network perspective of epigenetic regulation. The epigenetic mechanisms have important clinical implications and may provide insights into effective drug development and improve safety of drug therapy.

Regulation of drug metabolism and toxicity by multiple factors of genetics,epigenetics,lncRNAs,gut microbiota,and diseases:a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations(MDO)

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.

Preclinical experimental models of drug metabolism and disposition in drug discovery and development

Drug discovery and development involve the utilization of in vitro and in vivo ex perimental models.Different models,ranging from test tube experiments to cell cultures,animals,healthy human subjects,and even small numbers of patients that are involved in clinical trials,are used at different stages of drug discovery and development for determination of efficacy and safety.The proper selection and applications of correct models,as well as appropriate data interpretation,are critically important in decision making and succesful advancement of drug candidates.In this review,we discuss strategies in the applications of both in vitro and in vivo.experimental models of drug metabolism and disposition.

CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

The 2020 Nobel Prize in Chemistry recognized CRISPR-Cas9,a super-selective and precise gene editing tool.CRISPR-Cas9 has an obvious advantage in editing multiple genes in the same cell,and presents great potential in disease treatment and animal model construction.In recent years,CRISPRCas9 has been used to establish a series of rat models of drug metabolism and pharmacokinetics(DMPK),such as Cyp,Abcb1,Oatp1 b2 gene knockout rats.These new rat models are not only widely used in the study of drug metabolism,chemical toxicity,and carcinogenicity,but also promote the study of DMPK related mechanism,and further strengthen the relationship between drug metabolism and pharmacology/toxicology.This review systematically introduces the advantages and disadvantages of CRISPR-Cas9,summarizes the methods of establishing DMPK rat models,discusses the main challenges in this field,and proposes strategies to overcome these problems.

Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment

Remdesivir(RDV) is the only US Food and Drug Administration(FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated.We performed an in vitro and in vivo drug metabolism and pharmacokinetics(DMPK) assessment to examine the potential of RDV,and particularly GS-441524,as oral drugs.In our in vitro assessments,RDV exhibited prohibitively low stability in human liver microsomes(HLMs,t1/2=-1 min),with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety.This observation is poorly aligned with any potential oral use of RDV,though in the presence of cobicistat,the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH.Conversely,GS-441524 showed excellent metabolic stability in human plasma and HLMs.In further in vivo studies in CD-1 mice,GS-441524 displayed a favorable oral bioavailability of 57%.Importantly,GS-441524 produced adequate drug exposure in the mice plasma and lung,and was effectively converted to the active triphosphate,suggesting that it could be a promising oral antiviral drug for treating COVID-19.

EFFECT OF ANTIHYDATID DRUGS ON CARBOHYDRATE METABOLISM OF METACESTODE OF ECHINOCOCCUS GRANULOSUS

A biochemical some enzymes of glycolysis and a partial reversed tricarboxylic acid cycle together with hydrolytic enzymes in the cyst wall of Echinococcus granulosus was carried out. Lactate dehydrogenase (LDH), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), and adenosine triphosphatase (ATPase) showed their high level of activity, suggesting that the proliferation of E. granulosus cyst wall is an energy-dependent process and the major pathways for glucose metabolism is glycolysis. Treatment of E. granulosus-in-fected mice with mebendazole and albendazole resulted in marked inhibition of PK, PEPCK and ATPase of E. granulosus cyst wall, whereas praziquantel had no effect, indicating that PK, PEPCK, and ATPase might be chemotherapeutic targets and the differences in the inhibitory effects might account for the efficacy of the three antihydatid drugs.

Pregnane X receptor in drug-induced liver injury: Friend or foe?

The pregnane X receptor(PXR)is a ligand activated nuclear receptor that is highly expressed in the liver and regulates many cellular functions including drug metabolism,endobiotic metabolism,oxidative stress response,apoptosis,inflammation,cell proliferation and regeneration.PXR activation promotes drug-induced liver injury(DILI)through its ability to increase the expression of phaseⅠand phaseⅡdrug metabolizing enzymes.The PXR also increases lipid synthesis and fatty acid uptake into the liver,leading to lipid accumulation and steatosis.In recent years,PXR has been explored as an important target in DILI and liver diseases.This review will highlight the roles of PXR in modulating DILI.PXR polymorphisms that have been associated with DILI will also be discussed.