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

Summary: 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 48 hr at 2, 10, and 50  μ M. Analysis was performed by RT-PCR in the presence of TaqMan probe. CYP1A1 and CYP1A2 mRNA levels after exposure to 50  μ M omeprazole (positive control for CYP1As) were increased by 162 ( p p μ M rifampicin (positive control for CYP3As) were significantly increased by 5.8 ( p p μ M NO-1886 was increased by 1.3 times ( p μ M NO-1886 was significantly increased by 3.6 times (p  μ M NO-1886 was not significantly increased. CES1 and CES2 mRNA levels after exposure to 50  μ M NO-1886 were significantly increased by 1.4 ( p p μ M NO-1886 were significantly increased by 3.8 ( p p p μ M 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.