Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system.
The human liver bank has provided an invaluable model system for the study of interindividual variability in expression and activity of the major hepatic UGTs, including UGT1A1, 1A4, 1A6, 1A9, 2B7, and 2B15. Based on studies using UGT-isoform-selective probes, the rank order of activity variability is UGT 1A1>1A6>2B15>1A4 = 1A9>2B7, with coefficient of variation values ranging from 92 to 45%. Liver donor age, sex, enzyme inducers, and genetic polymorphism are factors that have been implicated as sources of this variability in UGT activity. The expression of UGTs prior to, and immediately following, birth is quite limited, explaining the susceptibility of neonates to certain drug toxicities. Old age appears to have minimal effect on UGT function. Sex differences in UGT activity are relatively small and are confined to several UGTs, including UGT2B15, which shows higher activity in males, compared with females. Enzyme inducers, including coadministered drugs, smoking, and alcohol, may increase hepatic UGT levels. Human liver bank phenotype-genotype studies, using UGT-isoform-selective probes have identified common genetic polymorphisms that are predictive of glucuronidation activity in vitro and that were subsequently verified as predictors of probe-drug clearance by glucuronidation in vivo.
Court
Michael H
MH
Laboratory of Comparative and Molecular Pharmacogenomics, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. michael.court@tufts.edu
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012727:Sex Characteristics; D014018:Tissue Distribution; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme