Forskolin-mediated induction of CYP3A1 mRNA expression in primary rat hepatocytes is independent of elevated intracellular cyclic AMP

Jaspreet S. Sidhu, Curtis J. Omiecinski

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24 Scopus citations

Abstract

Previously, we demonstrated that elevated levels of cyclic AMP (cAMP) repressed phenobarbital (PB)-inducible cytochrome P450 (CYP)2B gene expression in primary rat hepatocyte cultures. Although CYP3A1 induction by PB was similarly repressed by most of the cAMP-enhancing strategies, forskolin additions in particular resulted in marked stimulation of CYP3A1 expression. Here we examined whether this effect was due to forskolin's ability to activate adenylate cyclase. By using a specific ELISA for assessment of intracellular cAMP levels, we determined that forskolin and a water-soluble analog (L858051; 7β-desacetyl-7β-(N-methylpiperazine)) were equipotent in stimulating adenylate cyclase activity. However, only forskolin and its inactive 1,9-dideoxy analog were active as inducers of CYP3A1. In comparative studies, both dexamethasone and PB were ineffective in stimulating production of intracellular cAMP. Furthermore, treatment of hepatocytes with glucagon, dibutyryl-cAMP, or N6O2'-dibutyryl-cyclic GMP, resulted in no detectable enhancement of CYP3A1 gene expression. These results demonstrated that CYP3A1 induction by forskolin is independent of cAMP, and instead is likely to involve a direct chemical effect of forskolin on the CYP3A1 activation pathway.

Original languageEnglish (US)
Pages (from-to)238-245
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume276
Issue number1
StatePublished - Jan 1996

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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