title: Limited influence of UGT1A1*28 and no effect of UGT2B7*2 polymorphisms on UGT1A1 or UGT2B7 activities and protein expression in human liver microsomes.
abstract: OBJECTIVE
  UGT1A1 and UGT2B7 are enzymes that commonly contribute to drug glucuronidation. Since genetic factors have been suggested to contribute to variability in activities and expression levels of these enzymes, a quantitative assessment of the influence of the major genotypes (UGT1A1*28 or UGT2B7*2) on enzyme activities was conducted.
  
  
  METHODS
  Using a bank of microsomal samples from 59 human livers, the effect of UGT1A1*28 or UGT2B7*2 polymorphisms were investigated on rates of estradiol 3-glucuronidation (a marker of UGT1A1 enzyme activity) or zidovudine glucuronidation (a marker of UGT2B7 enzyme activity) and levels of immunoreactive protein for each enzyme. Glucuronidation rates for both enzymes were measured at K(m)/S(50) and 10 times K(m)/S(50) concentrations.
  
  
  RESULTS
  UGT1A1 and UGT2B7 enzyme activities varied up to 16-fold and sixfold, respectively. Rates at K(m)/S(50) concentration closely correlated with rates at 10 times K(m)/S(50) concentration for both enzymes (but not at 1/10th K(m) for UGT2B7). Enzyme activities correlated with relative levels of immunoreactive protein for UGT1A1 and UGT2B7. Furthermore, rates of zidovudine glucuronidation correlated well with rates of glucuronidation of the UGT2B7 substrate gemcabene, but did not correlate with UGT1A1 enzyme activities. For the UGT1A1*28 polymorphism, consistent with levels of UGT1A1 immunoreactive protein, mean UGT1A1 activity was 2.5- and 3.2-fold lower for TA(6)/TA(7) (P < 0.05) and TA(7)/TA(7) (P < 0.001) genotypes in comparison with the TA(6)/TA(6) genotype.
  
  
  CONCLUSIONS
  Relative to the observed 16-fold variability in UGT1A1 activity, these data indicate only a partial (approximately 40%) contribution of the UGT1A1*28 polymorphism to variability of interindividual differences in UGT1A1 enzyme activity. For the UGT2B7*2 polymorphism, genotype had no influence on immunoreactive UGT2B7 protein or the rate of 3'-azido-3'-deoxythymidine glucuronidation.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. vincent.peterkin@pfizer.com
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Peterkin
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Bauman
authors.forename: Theunis C
authors.initials: TC
authors.lastname: Goosen
authors.forename: Lee
authors.initials: L
authors.lastname: Menning
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Man
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Paulauskis
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Williams
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase