Characterization of a pretranscriptional pathway for induction by phenobarbital of cytochrome P450 3A23 in primary cultures of adult rat hepatocytes

Archives of Biochemistry and Biophysics
S E BrownP S Guzelian

Abstract

Our laboratory has proposed that phenobarbital (PB), a typical lipophilic agent that induces some members of the supergene family of liver microsomal cytochromes P450 (e.g., CYP2B1/2 and CYP3A23), acts through a complex process inhibitable by the presence of growth hormone (GH), the absence of some components of the extracellular matrix, or a disrupted cytoskeleton. To verify that these manipulations of the culture environment block specific steps in the PB induction pathway rather than simply exerting nonspecific or toxic effects on CYP2B1/2 gene transcription, we have now examined PB induction of CYP3A23, a gene known to also be transcriptionally activated by dexamethasone (DEX) through a "nonclassical" pathway apparently involving the glucocorticoid receptor. We found that in primary cultures of adult rat hepatocytes treated with PB, induction of CYP3A23 mRNA, just as we reported for induction of CYP2B1/2 mRNA, required the use of Matrigel (a reconstituted basement membrane) and was blocked by the presence of cytoskeletal inhibitors (colchicine or cytochalasins) or of physiologic concentrations of GH in the culture medium. Moreover, PB induction of CYP3A23 and of CYP2B1/2 mRNAs was greatly diminished by inhibitors of cAMP-de...Continue Reading

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Citations

Nov 2, 2002·British Journal of Pharmacology·Caroline FradettePatrick Du Souich
Jan 28, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Choon-Myung LeeEdward T Morgan
Feb 17, 2006·Annals of Clinical Microbiology and Antimicrobials·Jiezhong Chen, Kenneth Raymond
Oct 26, 1999·Biochemical and Biophysical Research Communications·A KawamuraA Kakinuma

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