Impact of dimethyl sulfoxide on expression of nuclear receptors and drug-inducible cytochromes P450 in primary rat hepatocytes.
Dimethyl sulfoxide (DMSO) is reported to induce hepatocyte redifferentiation. The impact of DMSO on liver transcription factors, cytochromes P450 (CYPs), and nuclear receptors regulating CYP expression was assayed in primary rat hepatocytes by QPCR. CYP 2B1, 3A1, and 4A1 mRNAs were reduced to 10-30% of initial liver levels without DMSO and restored at or above liver levels by DMSO treatment. In contrast, CYP1A1 mRNA increased approximately 5-fold during the course of culture, independent of DMSO. DMSO enhanced expression of the nuclear receptors CAR, PXR, and PPARalpha 2- to 5-fold, which may contribute to the increase in basal CYP expression. Without DMSO, liver transcription factors were decreased (HNF4, C/EBPalpha), largely unchanged (HNF1alpha, HNF3alpha, and C/EBPbeta) or elevated (HNF3beta, HNF6) compared to intact liver. DMSO largely restored hepatic levels of HNF4 and C/EBPalpha, partially suppressed the elevated levels of HNF6, increased HNF1alpha approximately 2-fold, and had little effect on HNF3alpha, HNF3beta, and C/EBPbeta. Overall, DMSO helped maintain normal hepatic transcription factor patterns and basal CYP and nuclear receptor profiles, suggesting that hepatocytes cultured with DMSO may be useful for CYP metabolic studies under conditions where the endogenous liver phenotype is preserved.
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Department of Biology, Division of Cell and Molecular Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA.
Waxman
David J
DJ
D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D004121:Dimethyl Sulfoxide