title: Effects of dimethyl sulfoxide on the gene induction of cytochrome P450 isoforms, UGT-dependent glucuronosyl transferase isoforms, and ABCB1 in primary culture of human hepatocytes.
abstract: We investigated the gene expression of GAPDH, cytochrome P450 isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7), UGT-dependent glucuronosyl transferase isoforms (UGT1A6 and UGT1A9), and ABC transporter (ABCB1) after exposure to 0.1, 0.5, and 2.5% dimethyl sulfoxide (DMSO). GAPDH mRNA levels after exposure were less than 2 times higher or lower than control levels at all DMSO concentrations. CYP1A1, CYP1B1, CYP2A6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, and UGT1A9 mRNA levels were less than 2 times higher or lower than control levels at 0.1% and 0.5% DMSO. CYP1A2, UGT1A6, and ABCB1 mRNA levels were less than 2 times higher or lower than control levels at all DMSO concentrations. CYP2E1 and CYP3A4 mRNA levels were 2.5-3.2 times and 2.0-3.3 times higher than control levels at 2.5% DMSO, respectively. UGT1A9 mRNA levels were 0.2-0.5 times lower than control levels at 2.5% DMSO. Exposure to beta-naphthoflavone reduced CYP1A1 mRNA levels in a concentration-dependent manner for donors 1 and 2. Exposure to beta-naphthoflavone reduced CYP1A2 mRNA levels in a concentration-dependent manner for all donors. However, exposure to beta-naphthoflavone increased CYP1B1 mRNA levels for donors 2 and 3 at 2.5% DMSO. Exposure to rifampicin reduced CYP3A4 mRNA levels for all donors at 0.5% and 2.5% DMSO. Exposure to rifampicin also reduced CYP3A5 and CYP3A7 mRNA levels for donors 1 and 3 at 0.5% and 2.5% DMSO. In conclusion, a DMSO concentration of 0.1% or less may be appropriate for studying induction after drug exposure.
authors.affiliation: Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima, Japan. nisimums@otsukakj.co.jp
authors.forename: Masuhiro
authors.initials: M
authors.lastname: Nishimura
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ueda
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Naito
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D018528:ATP-Binding Cassette Transporters; D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D004121:Dimethyl Sulfoxide