The use of hepatocytes to investigate UDP-glucuronosyltransferases and sulfotransferases

Since phase II reactions quantitatively represent the most important pathways involved in drug biotransformation, the development and the use of in vitro approaches to predict glucuronidation and sulfation are currently attracting intense interest to assist in the selection of new drug candidates and for the optimization of dosage regimens for established drugs. At present, primary cultures of human hepatocytes represent the most suitable in vitro model for drug metabolism studies. This system theoretically expresses the full complement of drug-metabolizing enzymes associated with the endoplasmic reticulum (CYP and UDP-glucuronosyltransferases) or located in the cytosolic compartment (sulfotransferases), and relevant accessory proteins required for drug transport and excretion. Primary hepatocytes also represent a unique in vitro model for global examination of inductive potential of drugs on conjugation reactions (monitored as increases in mRNA content or activity). The progress in cryopreservation over the last decade has made available preserved hepatocytes to address key issues such as the (i) establishment of phase II metabolic profile and rate, (ii) identification of conjugation enzymes involved, and (iii) evaluation of drug-drug interactions. These advances allow a better assessment of phase II reactions during drug discovery and development.