title: Bilirubin UDP-glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphisms and HPRT, glycophorin A, and micronuclei mutant frequencies in human blood.
abstract: A dinucleotide repeat polymorphism (5-, 6-, 7-, or 8-TA units) has been identified within the promoter region of UDP-glucuronosyltransferase 1A1 (UGT1A1) gene. The 7-TA repeat allele has been associated with elevated serum bilirubin levels that cause a mild hyperbilirubinemia (Gilbert's syndrome). Studies suggest that promoter transcriptional activity of UGT1A1 is inversely related to the number of TA repeats, and that unconjugated bilirubin concentration increases directly with the number of TA repeat elements. Because bilirubin is a known antioxidant, we hypothesized that UGT1A1 repeats associated with higher bilirubin may be protective against oxidative damage. We examined the effect of UGT1A1 genotype on somatic mutant frequency in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene in human lymphocytes and the glycophorin A (GPA) gene of red blood cells (both N0, NN mutants), and the frequency of lymphocyte micronuclei (both kinetochore (K)-positive or micronuclei K-negative) in 101 healthy smoking and nonsmoking individuals. As hypothesized, genotypes containing 7- and 8-TA displayed marginally lower GPA_NN mutant frequency relative to 5/5, 5/6, 6/6 genotypes ( [Formula: see text] ). In contrast, our analysis showed that lower expressing UGT1A1 alleles (7- and 8-TA) were associated with modestly increased HPRT mutation frequency ( [Formula: see text] ), while the same low-expression genotypes were not significantly associated with micronuclei frequencies (K-positive or K-negative) when compared to high-expression genotypes (5- and 6-TA). We found weak evidence that UGT1A1 genotypes containing 7- and 8-TA were associated with increased GPA_NØ mutant frequency relative to 5/5, 5/6, 6/6 genotypes ( [Formula: see text] ). These data suggest that UGT1A1 genotype may modulate somatic mutation of some types, in some cell lineages, by a mechanism not involving bilirubin antioxidant activity. More detailed studies examining UGT1A1 promoter variation, oxidant/antioxidant balance and genetic damage will be needed.
authors.affiliation: Environmental Genomics Section, Laboratory of Computational Biology and Risk Assessment, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Delores J
authors.initials: DJ
authors.lastname: Grant
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Hall
authors.forename: David A
authors.initials: DA
authors.lastname: Eastmond
authors.forename: Irene M
authors.initials: IM
authors.lastname: Jones
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D001769:Blood; D017931:DNA Primers; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006021:Glycophorins / Q000235:genetics*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D048629:Micronuclei, Chromosome-Defective; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D000099148:UGT1A1 Enzyme
chemical_list: D017931:DNA Primers; D014453:Glucuronosyltransferase; D006021:Glycophorins; D007041:Hypoxanthine Phosphoribosyltransferase; D000099148:UGT1A1 Enzyme