interacts_with DB01241?
Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole-cell patch-clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin-releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . DB00007 ( 10(-9)-10(-7) M ) , a specific DB00644 analog , concentration-dependently elicited a long-lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 -induced synaptic potentiation was blocked by 1 microM [ Acetyl-3,4-dehydro-Pro1,D-p-F-Phe2,D-Trp3,6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 -induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H-7 ) . The results suggest a long-term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes . Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators , e.g. DB00015 ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 ( e.g. P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility . Microarray analyses of the effects of NF-kappaB or PI3K pathway inhibitors on the LPS-induced gene expression profile in RAW264.7 cells : synergistic effects of rapamycin on LPS-induced P14780 -overexpression . Lipopolysaccharide ( LPS ) activates a broad range of signalling pathways including mainly NF-kappaB and the MAPK cascade , but recent evidence suggests that LPS stimulation also activates the PI3K pathway . To unravel the specific roles of both pathways in LPS signalling and gene expression profiling , we investigated the effects of different inhibitors of NF-kappaB ( BAY 11-7082 ) , PI3K ( wortmannin and LY294002 ) but also of P42345 ( rapamycin ) , a kinase acting downstream of PI3K/Akt , in LPS-stimulated RAW264.7 macrophages , analyzing their effects on the LPS-induced gene expression profile using a low density DNA microarray designed to monitor the expression of pro-inflammatory genes . After statistical and hierarchical cluster analyses , we determined five clusters of genes differentially affected by the four inhibitors used . In the fifth cluster corresponding to genes upregulated by LPS and mainly affected by BAY 11-7082 , the gene encoding P14780 displayed a particular expression profile , since rapamycin drastically enhanced the LPS-induced upregulation at both the mRNA and protein levels . DB00877 also enhanced the LPS-induced NF-kappaB transactivation as determined by a reporter assay , phosphorylation of the p38 and Erk1/2 MAPKs , and counteracted Q07869 activity . These results suggest that P42345 could negatively regulate the effects of LPS on the NF-kappaB and MAPK pathways . We also performed real-time RT-PCR assays on mmp9 expression using rosiglitazone ( agonist of PPARgamma ) , PD98059 ( inhibitor of Erk 1/2 ) and SB203580 ( inhibitor of p38(MAPK) ) , that were able to counteract the rapamycin mediated overexpression of mmp9 in response to LPS . Our results suggest a new pathway involving P42345 for regulating specifically mmp9 in LPS-stimulated RAW264.7 cells . Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre- and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high-performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50-88 % , P < 0.0005 ) and decreased P12268 ( 42-56 % , P < 0.0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P=0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 -treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1.26 vs. 0.87 respectively , P=0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation . A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 /5 and Q9BQB6 genes polymorphisms . DB00946 is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors . DB00946 metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms -1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 *2 and/or P11712 *3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 *1B , P20815 *3 and P20815 *6 polymorphisms . Among non-genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β-blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3.92 mg/week and 3.54 mg/week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm . GM- P04141 priming drives bone marrow-derived macrophages to a pro-inflammatory pattern and downmodulates DB00917 in response to O60603 ligands . In response to pathogen recognition by Toll-like receptors ( TLRs ) on their cell surface , macrophages release lipid mediators and cytokines that are widely distributed throughout the body and play essential roles in host responses . Granulocyte macrophage colony-stimulating factor ( GM- P04141 ) is important for the immune response during infections to improve the clearance of microorganisms . In this study , we examined the release of mediators in response to O60603 ligands by bone marrow-derived macrophages ( BMDMs ) primed with GM- P04141 . We demonstrated that when stimulated with O60603 ligands , non-primed BMDMs preferentially produced PGE(2) in greater amounts than Q06643 (4) . However , GM- P04141 priming shifted the release of lipid mediators by BMDMs , resulting in a significant decrease of PGE(2) production in response to the same stimuli . The decrease of PGE(2) production from primed BMDMs was accompanied by a decrease in PGE-synthase mRNA expression and an increase in P01375 -α and nitric oxide ( NO ) production . Moreover , some GM- P04141 effects were potentiated by the addition of IFN-γ . Using a variety of O60603 ligands , we established that PGE(2) release by GM- P04141 -primed BMDMs was dependent on O60603 co-receptors ( Q15399 , Q9Y2C9 ) , P08571 , MyD88 and the nuclear translocation of NFκB but was not dependent on peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) activation . Indeed , GM- P04141 priming enhanced O60603 , O00206 and MyD88 mRNA expression and phospho-IκBα formation . These findings demonstrate that GM- P04141 drives BMDMs to present a profile relevant to the host during infections . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . Lessons learned from the irinotecan metabolic pathway . DB00762 , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN-38 . SN-38 acts as a P11387 poison . DB00762 has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter-patient variability in irinotecan and SN-38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . DB00762 is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by P22309 to form SN-38G . The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan ( e.g. , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John 's Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e.g. , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent . Rosiglitazone affects nitric oxide synthases and improves renal outcome in a rat model of severe ischemia/reperfusion injury . Background. DB00435 ( NO ) -signal transduction plays an important role in renal ischemia/reperfusion ( I/R ) injury . NO produced by endothelial NO-synthase ( P29474 ) has protective functions whereas NO from inducible NO-synthase ( P35228 ) induces impairment . Rosiglitazone ( RGZ ) , a peroxisome proliferator-activated receptor ( Q07869 ) -γ agonist exerted beneficial effects after renal I/R injury , so we investigated whether this might be causally linked with NOS imbalance . Methods . RGZ ( 5 mg/kg ) was administered i.p. to SD-rats ( f ) subjected to bilateral renal ischemia ( 60 min ) . Following 24 h of reperfusion , inulin- and PAH-clearance as well as PAH-net secretion were determined . Morphological alterations were graded by histopathological scoring . Plasma NO(x)-production was measured . P29474 and P35228 expression was analyzed by qPCR . Cleaved caspase 3 ( Q9BUP3 ) was determined as an apoptosis indicator and Q92838 as a marker of macrophage infiltration in renal tissue . Results . RGZ improves renal function after renal I/R injury ( PAH-/inulin-clearance , PAH-net secretion ) and reduces histomorphological injury . Additionally , RGZ reduces NO(x) plasma levels , ED-1 positive cell infiltration and Q9BUP3 expression . P35228 -mRNA is reduced whereas P29474 -mRNA is increased by RGZ . Conclusion . RGZ has protective properties after severe renal I/R injury . Alterations of the NO pathway regarding P29474 and P35228 could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury . [ Innate resistance to thymidylate synthase inhibition after 5-fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of DB00322 MP binding sites of thymidylate thynthase ( TS-BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7-days administration of DB09327 ( U-7 group ) , total TS-BS was significantly increased compared with non-treatment group and the group received only DB09327 ( U-1 group ) . For free TS-BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U-7 group compared with U-1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg/kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect . 25-Hydroxycholesterol is not a ligand for the orphan nuclear receptor steroidogenic factor-1 ( Q13285 ) . The orphan nuclear receptor steroidogenic factor-1 ( Q13285 ) is involved in the transcriptional regulation of all the steroid hydroxylase genes , and also regulates the transcription of the genes for Müllerian Inhibitory substance ( P03971 ) , alpha subunit of glycoprotein hormone , LHbeta , oxytocin , P30968 , Q01718 , prolactin receptor , DAX-1 , and steroidogenic acute regulatory protein . Other members of the nuclear receptor gene family , including steroid hormone , thyroid hormone , retinoic acid , Q07869 , and vitamin D receptors must bind ligand to activate transcription , but Q13285 has been considered to be an orphan nuclear receptor because , when identified , it had no known ligand . A recent publication suggested that transcriptional regulation by Q13285 , expressed in a non-steroidogenic CV-1 cells , could be activated by oxysterols suggesting that these compounds could serve as natural ligands for Q13285 . We now demonstrate that 25-hydroxycholesterol , either added exogenously or synthesized endogenously in steroidogenic mouse Leydig MA-10 cells , did not act as a ligand for Q13285 , as it did not increase transcription from six different Q13285 -dependent DNA sequences . Furthermore , the abundance of these oxysterols in MA-10 cells was much less than concentrations needed for activation of Q13285 in CV-1 cells , indicating that Q13285 is not constitutively bound by ligand in MA-10 cells . Thus , in steroidogenic cells , transcriptional regulation of the steroid hydroxylase genes by Q13285 does not depend upon the presence of 25-hydroxycholesterol , and is not modified by its presence . A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 *3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol-sensitive patient was found to possess , in addition to P11712 *3 allele , a P11712 *11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions DB01418 sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare *11 allele . Q07869 gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease . BACKGROUND : Q07869 ( PPARalpha ) regulates the expression of genes involved in lipid metabolism and inflammation , making it a candidate gene for atherosclerosis and ischemic heart disease ( IHD ) . METHODS AND RESULTS : We investigated the association between the leucine 162 to valine ( L162V ) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the DB01241 Coronary Angiography Trial ( LOCAT ) , a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study ( Q9NP85 ) , a prospective study of healthy middle-aged men in the United Kingdom . There was no association with plasma lipid concentrations in either study . Both polymorphisms influenced progression of atherosclerosis and risk of IHD . V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis . Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes . The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele . Homozygotes for the intron 7 C allele had increased risk of IHD , an effect modulated by the L162V polymorphism CONCLUSIONS : The PPARalpha gene affects progression of atherosclerosis and risk of IHD . Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall . Desmopressin ( DB00035 ) induces NO production in human endothelial cells via V2 receptor- and DB02527 -mediated signaling . The hemostatic agent desmopressin ( DB00035 ) also has strong vasodilatory effects . DB00035 is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 -dependent signaling . DB00035 -induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 -mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 -raising agents forskolin and epinephrine increase NO production , as measured by a l-NMMA-inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium-independent manner . DB02527 -mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3-kinase ( PI3K ) -independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , DB00035 induces DB02527 -dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT-PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that DB00035 and other DB02527 -raising agents can activate P29474 via PI3K-independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for DB00035 -induced vasodilation . Integrative analysis of transcriptomics , proteomics , and metabolomics data of white adipose and liver tissue of high-fat diet and rosiglitazone-treated insulin-resistant mice identified pathway alterations and molecular hubs . The incidences of obesity and type 2 diabetes are rapidly increasing and have evolved into a global epidemic . In this study , we analyzed the molecular effects of high-fat diet ( HFD ) -induced insulin-resistance on mice in two metabolic target tissues , the white adipose tissue ( WAT ) and the liver . Additionally , we analyzed the effects of drug treatment using the specific PPARγ ligand rosiglitazone . We integrated transcriptome , proteome , and metabolome data sets for a combined holistic view of molecular mechanisms in type 2 diabetes . Using network and pathway analyses , we identified hub proteins such as P21912 and P53597 in WAT and deregulation of major metabolic pathways in the insulin-resistant state , including the TCA cycle , oxidative phosphorylation , and branched chain amino acid metabolism . Rosiglitazone treatment resulted mainly in modulation via Q07869 signaling and oxidative phosphorylation in WAT only . Interestingly , in HFD liver , we could observe a decrease of proteins involved in vitamin B metabolism such as Q6P996 and P00374 and the according metabolites . Furthermore , we could identify sphingosine ( Sph ) and sphingosine 1-phosphate ( SP1 ) as a drug-specific marker pair in the liver . In summary , our data indicate physiological plasticity gained by interconnected molecular pathways to counteract metabolic dysregulation due to high calorie intake and drug treatment . Obesity and breast cancer : the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1 . Breast cancer is the most prominent cancer among females in the United States . There are a number of risk factors associated with development of breast cancer , including consumption of a high-fat diet and obesity . P00747 activator inhibitor-1 ( P05121 ) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer . As a key mediator of adipogenesis and regulator of adipokine production , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) is involved in P05121 expression from adipose tissue . We summarize the current knowledge linking Q07869 -γ and P05121 expression to high-fat diet and obesity in the risk of breast cancer . Peroxisome proliferator-activated receptor ( Q07869 )α and -γ regulate IFNγ and Q16552 production by human T cells in a sex-specific way . Women develop certain autoimmune diseases more often than men . It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women . To test whether women exhibit a Th1 bias , we isolated naïve cluster of differentiation (CD)4(+) T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti- P10747 . We observed that P01730 (+) T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male P01730 (+) T cells . Intriguingly , male P01730 (+) T cells instead had a predilection toward Q16552 production . This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory ( SJL ) mouse . Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activated receptor ( Q07869 )α and PPARγ . Androgens increased PPARα and decreased PPARγ expression by human P01730 (+) T cells . PPARα siRNA-mediated knockdown had the effect of increasing IFNγ by male P01730 (+) T cells , while transfection of P01730 (+) T cells with PPARγ siRNAs increased Q16552 production uniquely by female T cells . Together , our observations indicate that human T cells exhibit a sex difference in the production of IFNγ and Q16552 that may be driven by expressions of PPARα and PPARγ . Systems pharmacology assessment of the 5-fluorouracil pathway . AIM : To assess the impact of the 5-fluorouracil ( DB00544 ) drug-pathway genes on cytotoxicity , and determine whether loss-of-function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose-response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) for control-treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples . The O60656 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene . Peroxisome proliferator-activated receptor ( Q07869 ) alpha and gamma are ligand-activated transcription factors belonging to the nuclear receptor family . Q07869 alpha mediates the hypolipidemic action of the fibrates , whereas Q07869 gamma is a receptor for the antidiabetic glitazones . In the present study , the UDP-glucuronosyltransferase ( P78381 ) 1A9 enzyme is identified as a Q07869 alpha and Q07869 gamma target gene . UGTs catalyze the glucuronidation reaction , which is a major pathway in the catabolism and elimination of numerous endo- and xenobiotics . Among the P22309 family enzymes , O60656 metabolizes endogenous compounds , including catecholestrogens , and xenobiotics , such as fibrates and to a lesser extent troglitazone . Treatment of human hepatocytes and macrophages and murine adipocytes with activators of Q07869 alpha or Q07869 gamma resulted in an enhanced O60656 expression and activity . In addition , disruption of the Q07869 alpha gene in mice completely abolished the Q07869 alpha agonist-induced O60656 mRNA and activity levels . A Q07869 response element was identified in the promoter of O60656 at positions -719 to -706 bp by transient transfection and electromobility shift assays . Considering the role of O60656 in catecholestrogen metabolism , Q07869 alpha and Q07869 gamma activation may contribute to the protection against genotoxic catecholestrogens by stimulating their inactivation in glucuronide derivatives . Furthermore , since O60656 is involved in the catabolism of fibrates , these results suggest that Q07869 alpha and Q07869 gamma may control the intracellular level of active fibrates .