期刊
DRUG METABOLISM AND DISPOSITION
卷 38, 期 12, 页码 2166-2172出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.110.035501
关键词
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资金
- National Institutes of Health National Institute for General Medical Science [R01-GM069971]
- National Institutes of Health National Institute for Diabetes and Digestive and Kidney Diseases [N01-DK70004/HHSN267200700004C]
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.
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