Thesis (Ph. D.)--University of Wisconsin--Madison, 1975. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

<p>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.</p><p>Three different methods for genotyping of UGT1A1*28 have been tested.</p><p>PCR with electrophoresis used for size separation, melting temperature analysis and fluorescent PCR followed by fragment analysis on a capillary sequencer.</p><p>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).</p><p>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.<strong> </strong></p><p><strong> </strong></p> / <p>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.</p><p>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).</p><p>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 ökad risk för biverkningar av irinotekan.</p>

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&lt;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 ökad risk för biverkningar av irinotekan.

Xenobiotic biotransformation process and its capacity is crucial for xenobiotic chemicals elimination that may cause damage toward cell structures. The effectiveness of the enzymes included in this process depends on the gene variants that encodes them. The aim of this work was to compare certain polymorphisms of selected genes between cases and control groups. Studied polymorphisms were null genotypes of the glutathione S-transferase gene M1 and T1 and the insertion of TA dinucleotide in the promotor region of UDP-glucuronosyl transferase 1A1. The number of cases group was six included patients with colorectal, lung, prostate, breast, pancreatic and head and neck cancer. Total number of analysed individuals was 1 118 for cancer cases and 470 for healthy controls. The control group was divided into two groups, the first one was called general and the second one was called special included healthy individuals with no cancer history in their closest family members. Gilbert syndrome (GS) is caused by homozygous insertion of the TA dinucleotide in the TATA box of the gene UGT1A1 and it causes elevated bilirubin levels. Bilirubin is a potent antioxidant in human body, so the aim was to attest its protective effect toward cancer. We expected lower frequency of GS as a protective factor in the cases groups compared with controls. This hypothesis was confirmed in the breast cancer group (GS frequency 10,0 %) and pancreatic cancer group (GS frequency 11,1 %). In the general and special control groups the frequency of GS was 16,0 % and 15,4 % respectively. Although the other case groups show lower frequency of GS, the results weren´t statistically significant. Null GSTM1 genotype was observed with 50,4 % frequency in the general control groups and with 55,3 % frequency in the special control group. Neither the one of the cases groups hasn´t showed significantly lower percentage of null genotype. Despite expectation we observed statistically significant lower frequency of null genotype in the group of lung and pancreatic cancer group (37,4 % and 39,3 % respectively). According to this study, we can say that the lack of glutathione S-transferase M1 activity is not a risk factor for cancer development. Null genotype of GSTT1 wasn´t identified in both control groups at all. In case groups of breast and prostate cancer, there was only one individual carrying the null GSTT1 genotype. Statistically significant higher frequency of this polymorphism was observed in patients with colorectal cancer (9,7 %), lung cancer (17,2 %), pancreatic cancer (3,0 %) and head and neck cancer (15,9 %). In these groups the lack of glutathion S-transferase T1 activity might be considered as risk factor for cancer development. Nevertheless, for further verification it needs to take more investigation in this field, especially enlarge the number of patient in the case groups of head and neck, lung and pancreatic cancer.

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