title: UGT1A1*28 genotype affects the in-vitro glucuronidation of thyroxine in human livers.
abstract: OBJECTIVE
  L-thyroxine (T4), the most widely used drug for hypothyroidism, undergoes glucuronidation by UDP-glucuronosyltransferases. Clinical evidence obtained after the administration of anticonvulsants suggest that glucuronidation may play an important role in T4 homeostasis in humans. The aims of this study were to determine the T4 glucuronidation ability of all commercially available human UGTs, and investigate the relationship between genetic polymorphisms in UGT1A1 and UGT1A9 and T4 glucuronidation in human livers.
  
  
  METHODS
  Glucuronidation of T4 in human liver microsomes and recombinant UDP-glucuronosyltransferases was measured by high-pressure liquid chromatography. UGT1A1 -53(TA)6>7 (UGT1A1*28) and UGT1A9 -118T9>10 (UGT1A9*1b) variants were genotyped by polymerase chain reaction and sizing.
  
  
  RESULTS
  A strong correlation was observed between the glucuronidation of T4 and SN-38, a UGT1A1 substrate (r=0.82, P<0.0001). A significant trend of decreasing T4 glucuronide (T4G) levels was observed with increasing number of UGT1A1 -53(TA)7 alleles (P=0.001). Other hepatic UDP-glucuronosyltransferases involved in T4G formation are UGT1A3 and UGT1A9. No significant relationship was observed between UGT1A9 -118T9>10 and T4 glucuronidation activity. T4 can also undergo glucuronidation by UGT1A8 and UGT1A10, which are expressed in the gastrointestinal tract (but not the liver) and may be important for first-pass T4 metabolism.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Yoder Graber
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D018076:DNA, Complementary; D005419:Flavonoids / Q000378:metabolism; D005838:Genotype; D005965:Glucuronates / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D010641:Phenotype; D010880:Piperidines / Q000378:metabolism; D011110:Polymorphism, Genetic; D013974:Thyroxine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D018076:DNA, Complementary; D005419:Flavonoids; D005965:Glucuronates; D020719:Glucuronides; D014453:Glucuronosyltransferase; D010880:Piperidines; D013974:Thyroxine; D000099148:UGT1A1 Enzyme; C106003:SN38-Glu; C054785:thyroxine glucuronide; C077990:alvocidib