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

Abstract

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.

Keywords::

• Liver
• glucuronidation
• variability
• pharmacogenetics
• sex
• age

Acknowledgements

MHC was supported by grant GM-061834 from the National Institute of General Medical Sciences (NIGMS), National Institutes of Health (Bethesda, Maryland, USA). Chantal Guillemette and Hugo Girard are gratefully acknowledged for their contributions to several collaborative projects, involving UGT genotype-phenotype analyses of the Tufts human liver bank. Su Duan, Qin Hao, Leah Hesse, Ping He, Xi He, and Soundar Krishnaswamy are also acknowledged for their role in generating much of the UGT genotype-phenotype data. David Greenblatt and Lisa von Moltke were also instrumental in setting up the Tufts liver bank.

Declaration of interest: The work described here was supported in the part by grants from the National Institutes of Health (Bethesdd, Maryland, USA) and Pfizer Global Research and Development (San Diego, California, USA).