Title : Involvement of cyclic nucleotide- and calcium-regulated pathways in phenobarbital-induced cytochrome P-450 3A expression in mouse primary hepatocytes.

Pub. Date : 1999 Sep

PMID : 10454503






9 Functional Relationships(s)
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1 Several of the hepatic microsomal cytochromes P-450 (CYP) including CYP3A are inducible by phenobarbital (PB). Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
2 Several of the hepatic microsomal cytochromes P-450 (CYP) including CYP3A are inducible by phenobarbital (PB). Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
3 However, the intracellular pathways involved in the action of PB on CYP3A remain poorly known. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
4 With the aim to unravel some of the main aspects of PB signaling, we first devised a simple model of mouse cultured primary hepatocytes in which CYP3A mRNA and protein were strongly induced by PB in the absence of dexamethasone and were at maximum levels after a 48-h treatment with a 2-mM dose of PB. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
5 With the aim to unravel some of the main aspects of PB signaling, we first devised a simple model of mouse cultured primary hepatocytes in which CYP3A mRNA and protein were strongly induced by PB in the absence of dexamethasone and were at maximum levels after a 48-h treatment with a 2-mM dose of PB. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
6 With the aim to unravel some of the main aspects of PB signaling, we first devised a simple model of mouse cultured primary hepatocytes in which CYP3A mRNA and protein were strongly induced by PB in the absence of dexamethasone and were at maximum levels after a 48-h treatment with a 2-mM dose of PB. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
7 Under these culture conditions, we studied the effects of inhibitors and activators of different protein kinases or phosphatases on CYP3A mRNA and protein induction by PB. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
8 Inhibition of Ca(2+)/calmodulin-dependent protein kinase by KN-62 or the intracellular Ca(2+) chelator BAPTA-AM produced an inhibition of CYP3A induction by PB. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus
9 Taken together, our results suggest that CYP3A induction by PB is regulated positively by calmodulin-dependent protein kinase and cGMP-dependent protein kinase, and negatively by PKA in mouse hepatocytes in primary culture. Phenobarbital cytochrome P450, family 3, subfamily a, polypeptide 11 Mus musculus