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.
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.
Nishimura
Masuhiro
M
Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima, Japan. nisimums@otsukakj.co.jp
Ueda
Nobuhiko
N
Naito
Shinsaku
S
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
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