Effects of NO-1886 (Ibrolipim), a Lipoprotein Lipase-Promoting Agent, on Gene Induction of Cytochrome P450s, Carboxylesterases, and Sulfotransferases in Primary Cultures of Human Hepatocytes

• Published in: Drug metabolism and pharmacokinetics Vol. 19; no. 6; pp. 422 - 429
• Main Authors: Nishimura, Masuhiro, Imai, Teruko, Morioka, Yujiro, Kuribayashi, Shunji, Kamataki, Tetsuya, Naito, Shinsaku
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 2004
• Subjects: Benzamides - pharmacology; carboxylesterase; Carboxylic Ester Hydrolases - biosynthesis; Carboxylic Ester Hydrolases - genetics; Cells, Cultured; cryopreserved human hepatocytes; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; cytochrome P450; Hepatocytes - enzymology; Hepatocytes - metabolism; Humans; Isoenzymes - biosynthesis; Isoenzymes - genetics; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; mRNA induction; NO-1886; Oligonucleotides - metabolism; Organophosphorus Compounds - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Stimulation, Chemical; sulfotransferase; Sulfotransferases - biosynthesis; Sulfotransferases - genetics; mRNA induction; cryopreserved human hepatocytes; carboxylesterase; cytochrome P450; sulfotransferase; NO-1886
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.19.422

In the present study, the effects on expression of cytochrome P450 (CYP1A1, CYP1A2, CYP3A4 and CYP3A5), carboxylesterase (CES1 and CES2) and sulfotransferase (CHST1, CHST3, CHST4, CST, SULT2A1 and TPST2) mRNA in primary cultures of cryopreserved human hepatocytes were evaluated after exposure to NO-1886 (diethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzyl-phosphonate) for 48hr at 2, 10, and 50μM. Analysis was performed by RT-PCR in the presence of TaqMan probe. CYP1A1 and CYP1A2 mRNA levels after exposure to 50μM omeprazole (positive control for CYP1As) were increased by 162 (p<0.001) and 37 times (p<0.001), respectively, compared with untreated controls. However, these mRNA levels were increased by 2 times or less after exposure to NO-1886. CYP3A4 and CYP3A5 mRNA levels after exposure to 50μM rifampicin (positive control for CYP3As) were significantly increased by 5.8 (p<0.01) and 2.0 times (p<0.01), respectively, compared with untreated controls. The CYP3A4 mRNA level after exposure to 10μM NO-1886 was increased by 1.3 times (p<0.05). Further, the CYP3A4 mRNA level after exposure to 50μM NO-1886 was significantly increased by 3.6 times (p<0.001). However, the CYP3A5 mRNA level after exposure to 50μM NO-1886 was not significantly increased. CES1 and CES2 mRNA levels after exposure to 50μM NO-1886 were significantly increased by 1.4 (p<0.05) and 2.6 times (p<0.01), respectively, compared with untreated controls. CHST1, CST and SULT2A1 mRNA levels after exposure to 50μM NO-1886 were significantly increased by 3.8 (p<0.001), 1.8 (p<0.01) and 4.4 times (p<0.01), respectively. CHST3, CHST4 and TPST2 mRNA levels after exposure to 50μM NO-1886 were not significantly increased. This in vitro technique using primary cultured human hepatocytes is expected to be very useful for the preclinical evaluation of the induction of drug-metabolizing enzymes in humans.