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You searched for subject:(UDP glucuronosyl transferase). Showing records 1 – 3 of 3 total matches.

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University of Helsinki

1. Hirvisaari, Laura. Katekoliestradiolien glukuronidaatio.

Degree: Farmaceutiska fakulteten, 2012, University of Helsinki

Estradioli on naisten tärkein naissukupuolihormoni, ja se metaboloituu elimistössä kahdeksi katekoliestradioliksi. 2-hydroksiestradioli (2-OHE2) on normaalisti vallitseva estradiolin katekolimetaboliitti, mutta rintasyöpäpotilailla genotoksinen 4-hydroksiestradioli (4-OHE2) kohoaa vallitsevaksi katekoliestradiolimetaboliitiksi. Molemmat katekoliestradiolit muodostavat reaktiivisia kinoneja, jotka voivat DNA:ta vaurioittamalla johtaa mutaatioihin ja lopulta syövän kehittymiseen. 4-OHE2:n karsinogeenisuuden syyt eivät ole vielä täysin selvillä, mutta 4-OHE2:sta muodostuu enemmän DNA:ta vaurioittavia kinoneja. Faasi II metaboloivat entsyymit voivat inaktivoida muodostuvia katekoliestradioleita metyloimalla (COMT) tai liittämällä substraattiin glukuronihapon (UGT:t). Nämä faasi II entsyymit voivat näin suojata rintasyövältä, sillä ainoastaan konjugoimattomat katekoliestradiolit voidaan hapettaa reaktiivisiksi kinoneiksi. Tässä työssä tutkittiin ihmisen UDP-glukuronosyylitransferaasien (UGT) katalysoimia glukuronidaatioreaktioita katekoliestradioleiden kanssa. Tätä varten 2-OHE2:n ja 4-OHE2:n glukuronideille kehitettiin omat HPLC-menetelmänsä. 2-OHE2:lla havaittiin kahta eri glukuronidia. 11 UGT-isoentsyymiä katalysoi 2-OHE2:n glukuronidaatiota, ja näistä UGT:t 1A1, 1A7 ja 1A10 muodostavat molempia glukuronideja. UGT:t 1A3, 1A8, 1A9, 2A1, 2A2, 2A3, 2B7 ja 2B15 muodostavat ainoastaan toisena retentoitunutta glukuronidia, joka oli vallitseva glukuronidi myös UGT1A1:llä, UGT1A7:llä ja UGT1A10:llä. 4-OHE2:lla muodostui kolmea eri glukuronidia, mutta ensimmäisen glukuronidin pitoisuudet jäivät alle kvantitointirajan. UGT1A10 katalysoi toisena ja UGT:t 1A7, 1A8, 1A9, 2B7 ja 2B15 katalysoivat kolmantena retentoitunutta glukuronidia. Tavoitteena oli myös selvittää mihin hydroksyyliryhmään glukuronidi kiinnittyy, mutta tämä tavoite jäi saavuttamatta, sillä sopivia standardeja ei ollut saatavilla.

Subjects/Keywords: UGT; HPLC; Catechol estradiols; glucuronidation; 2-hydroxyestradiol; 4-hydroxyestradiol; UDP-glucuronosyl transferase; separation method development; glukuronidaatio; 2-hydroksiestradioli; 4-hydroksiestradioli; UDP-glukuronosyylitransferaasi; kromatografiamenetelmä; katekoliestradioli; Farmaceutisk kemi; Pharmaceutical Chemistry; Farmaseuttinen kemia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Hirvisaari, L. (2012). Katekoliestradiolien glukuronidaatio. (Masters Thesis). University of Helsinki. Retrieved from http://hdl.handle.net/10138/35742

Chicago Manual of Style (16th Edition):

Hirvisaari, Laura. “Katekoliestradiolien glukuronidaatio.” 2012. Masters Thesis, University of Helsinki. Accessed January 23, 2021. http://hdl.handle.net/10138/35742.

MLA Handbook (7th Edition):

Hirvisaari, Laura. “Katekoliestradiolien glukuronidaatio.” 2012. Web. 23 Jan 2021.

Vancouver:

Hirvisaari L. Katekoliestradiolien glukuronidaatio. [Internet] [Masters thesis]. University of Helsinki; 2012. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/10138/35742.

Council of Science Editors:

Hirvisaari L. Katekoliestradiolien glukuronidaatio. [Masters Thesis]. University of Helsinki; 2012. Available from: http://hdl.handle.net/10138/35742


Uppsala University

2. Fredriksson, Lena. IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)n.

Degree: Medical Biochemistry and Microbiology, 2009, Uppsala University

Gilbert’s syndrome (GS) occurs in approximately 10% of the European population. The most common cause is homozygosity for UGT1A1*28, which is a TA repeat expansion in the promoter of UGT1A1. It is characterised by intermittent hyperbilirubinemia due to reduced hepatic activity of the  enzyme UDP-glucuronosyl-transferase 1A1(UGT1A1). GS also  alteres the pharmacokinetics of some drugs and increases the risk of drug toxicity. Irinotecan (Camptosar®, Campto®) is used in metastatic colorectal cancer and the active metabolite is inactivated by UGT1A1. Studies have shown that GS can be a risk factor for toxicity during irinotecan therapy. Three different methods for genotyping of UGT1A1*28 have been tested. PCR with electrophoresis used for size separation, melting temperature analysis and fluorescent PCR followed by fragment analysis on a capillary sequencer. The last method was found to be superior. This method was used for genotyping of patients with colorectal cancer treated with irinotecan and 5-fluorouracil in the Nordic VI study. A significant association between UGT1A1 genotype and plasma bilirubin level before the start of irinotecan treatment was seen (ANOVA p<0.0001). Patients with GS had an overall increased risk of adverse drug reactions (Fishers Exact test p=0.02). Gilbert’s syndrome can be diagnosed by genotyping UGT1A1*28 with a fragment analysis method. Genotyping of UGT1A1*28 can be used to identify patients with an increased risk of adverse reactions to irinotecan.

Gilberts syndrom (GS) drabbar upp till 10% av befolkningen i Västeuropa. GS beror på nedsatt aktivitet av enzymet UDP-glukuronosyltransferas 1A1 (UGT1A1) i levern. Den vanligaste orsaken är att individen är homozygot för en insertion av två baser i promotorn för genen UGT1A1. Denna genvariant kallas (TA)7TAA  eller UGT1A1*28. GS leder till intermittent stegring av bilirubin vid infektioner, men bilirubinstegring kan förekomma även utan utlösande agens. GS kan också leda till bilirubinstegring vid viss läkemedelsbehandling. Irinotekan (Campto®) används vid metastaserande colorektal cancer och dess aktiva metabolit inaktiveras av UGT1A1. Det finns rapporter om att GS ger ökad risk för toxiska biverkningar av irinotekan. Tre metoder för att bestämma UGT1A1 har jämförts: PCR med elfores, PCR med smältpunktsanalys och PCR med fragmentanalys på sekvensator. Den sista metoden var bäst och användes för att genotypa UGT1A1 hos patienter med colorektal cancer från Nordic VI-studien. De behandlades med irinotekan i kombination med bolusinjektion eller infusion av 5-fluorouracil. Vi fann att  patienter med GS hade signifikant högre S-bilirubin före behandling jämfört med övriga patienter. De hade även ökad frekvens biverkningar av irinotekan (Fishers exakta test p=0,02). Genotypning av UGT1A1 kan således användas för att diagnostisera Gilberts syndrom hos patienter med oförklarad bilirubinstegring. Det kan även användas för att identifiera patienter med…

Subjects/Keywords: Fragment analysis; genetic analysis; Gilbert´s syndrome; irinotecan; TATA box; UDP Glucuronosyl-transferase 1A1; UGT1A1 *28; Pharmacology and Toxicology; Farmakologi och toxikologi

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Fredriksson, L. (2009). IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)n. (Thesis). Uppsala University. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107558

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Fredriksson, Lena. “IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)n.” 2009. Thesis, Uppsala University. Accessed January 23, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107558.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Fredriksson, Lena. “IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)n.” 2009. Web. 23 Jan 2021.

Vancouver:

Fredriksson L. IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)n. [Internet] [Thesis]. Uppsala University; 2009. [cited 2021 Jan 23]. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107558.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fredriksson L. IRINOTECANTOXICITY RELATED TO GILBERT´S SYNDROME   - COMPARISON OF THREE METHODS FOR GENOTYPING OF UGT1A1 (TA)n. [Thesis]. Uppsala University; 2009. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107558

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


University of Cincinnati

3. Sane, Rucha S. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.

Degree: PhD, Pharmacy : Pharmaceutical Sciences, 2006, University of Cincinnati

Tamoxifen is a widely used antiestrogen in the treatment and prevention of breast cancer. Some of its unresolved problems include the occurrence of drug-drug interactions, acquired resistance and endometrial carcinogenesis. Here we hypothesized that tamoxifen and/or its metabolites induce drug metabolizing enzymes and transporters and these inductive effects entail activation of the human pregnane X receptor (hPXR). First, we evaluated the activity and expression of key phase I and II enzymes, Cytochrome P450 (CYP) 3A4 and UDP-Glucuronyltransferase and drug transporter, P-glycoprotein, in primary human hepatocytes and LS174T colon carcinoma cell line. Tamoxifen and 4-hydroxytamoxifen (4-OHT) exhibited significant induction of CYP3A4 and moderate induction of UGT1A1 and P-gp in hepatocytes. In LS174T cells tamoxifen/4OHT moderately induced UGT1A1 and P-gp but failed to induce CYP3A4. This apparent tissue-specific difference in CYP3A4 induction by tamoxifen may be related to the observed differences in the expression of transcription factors such as hPXR and glucocorticoid receptor in (GRá) these cells. Next, in promoter-reporter assays we observed that tamoxifen/4-OHT are efficient activators of hPXR. Attenuation of hPXR in human hepatocytes employing siRNA against hPXR caused a corresponding decrease in the extent of CYP3A4 induction indicating that induction by tamoxifen/4-OHT primarily results from their interactions with hPXR. Examination of the role of other receptors revealed that GRá potentiates hPXR mediated CYP3A4 promoter activation by the antiestrogens. However, activated estrogen receptor appeared to suppress the basal transcription of CYP3A4 in these assays. Based on our pre-clinical data, we initiated a clinical study to assess CYP3A4 induction in breast cancer patients who are prescribed the tamoxifen regimen (20 mg/day). Midazolam, a drug metabolized by CYP3A4, was employed as a probe for CYP3A4 activity. In four patients evaluated thus far, we have noted a distinct trend towards increased midazolam clearance, indicative of increased CYP3A4 activity, following steady state tamoxifen dosing (day 42) compared to basal CYP3A4 activity, evaluated prior to initiating tamoxifen therapy. Thus, our study suggests that tamoxifen/4-OHT upregulate CYP3A4, which has implications for optimizing the clinical use of tamoxifen and the development of new antiestrogens that do not carry the risk of drug interactions, acquired drug resistance and endometrial carcinogenesis. Advisors/Committee Members: Desai, Rucha (Advisor).

Subjects/Keywords: Health Sciences, General; Tamoxifen; CYP3A4; Cytochrome P450; Enzyme induction; drug metabolism; human hepatocytes; UDP-glucuronosyl transferase; P-glycoprotein; Pregnane X Receptor; PXR; LS174T

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Sane, R. S. (2006). Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

Chicago Manual of Style (16th Edition):

Sane, Rucha S. “Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.” 2006. Doctoral Dissertation, University of Cincinnati. Accessed January 23, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

MLA Handbook (7th Edition):

Sane, Rucha S. “Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications.” 2006. Web. 23 Jan 2021.

Vancouver:

Sane RS. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. [Internet] [Doctoral dissertation]. University of Cincinnati; 2006. [cited 2021 Jan 23]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

Council of Science Editors:

Sane RS. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. [Doctoral Dissertation]. University of Cincinnati; 2006. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

.