RT Journal Article
SR Electronic
T1 Metabolism and Action of Proteasome Inhibitors in Primary Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2166
OP 2172
DO 10.1124/dmd.110.035501
VO 38
IS 12
A1 Choon-Myung Lee
A1 Vikas Kumar
A1 Rochelle I. Riley
A1 Edward T. Morgan
YR 2010
UL http://dmd.aspetjournals.org/content/38/12/2166.abstract
AB Proteasome inhibitors are important tools for studying the roles of the proteasome in cellular processes. In this study, we observed that the proteasome inhibitors N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), epoxomicin, and lactacystin were ineffective and bortezomib was completely effective in inhibiting cytokine-stimulated nitric oxide production in primary cultures of human hepatocytes that had been treated with the cytochrome P450 inducer phenobarbital. The inefficacy of MG132 was due to its metabolism by CYP3A enzymes, as deduced from its rapid, ketoconazole-sensitive clearance by pooled human liver microsomes and cultured hepatocytes. The efficacy of MG132 was increased by inclusion of ketoconazole in the hepatocyte incubations and decreased by prior treatment of the cultures with the CYP3A inducers phenobarbital or rifampicin. Epoxomicin was also rapidly metabolized by CYP3A, whereas bortezomib and lactacystin were much more stable metabolically in human liver microsomes or hepatocyte cultures. Thus, bortezomib is a better choice than MG132, epoxomicin, or lactacystin in cells with high activities of CYP3A enzymes. The reason for the lack of efficacy of lactacystin in human hepatocytes has yet to be determined, but it too should not be used for studies of proteasome function in human hepatocytes.