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The expression of CYP2C12 is liver-specific and
regulated at the transcriptional level by growth hormone (GH). In
attempts to elucidate the nature of signaling molecules mediating the
GH regulation of this gene in rat hepatocytes, a role for phospholipase
A
Volume 270,
Number 21,
Issue of May 26, pp. 12569-12577, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
(PLA) as a transducer of GH-induced levels of
P4502C12 mRNA was investigated. GH was shown to induce
tyrosyl-phosphorylation of p42 and p44 microtubule-associated protein
(MAP) kinases and to reduce the electrophoretic mobility of a 100-kDa
protein, immunologically related to cPLA. These events were
observed in parallel with GH-stimulated release of
[
H]arachidonic acid ([H]AA)
from cellular phospholipids of rat hepatocytes labeled with
[H]AA. These rapid effects of GH action, as well
as the GH-induced expression of CYP2C12, were inhibited in
cells treated with the tyrosine kinase inhibitor herbimycin A.
Similarly, when the GH-induced liberation of
[H]AA was blocked by the PLA inhibitor mepacrine or the Ca channel blocker
verapamil, GH-induced accumulation of P4502C12 mRNA was absent. These
results suggest a correlation between PLA
activity and GH
regulation of the CYP2C12 gene. The inhibitory effect of
mepacrine on GH induction of P4502C12 mRNA was reversed by AA addition,
further supporting a role for eicosanoids in the regulation of
CYP2C12. Finally, inhibitors of P450-mediated AA metabolism,
SKF-525A and ketoconazole as well as eicosatetraynoic acid, blocked the
GH-mediated induction of P4502C12 mRNA, whereas more specific
inhibitors of cyclooxygenase or lipoxygenase metabolism did not. Based
on these results, we suggest that GH signaling in rat hepatocytes,
leading to increased expression of CYP2C12, involves PLA activation and subsequent P450-catalyzed formation of an active
AA metabolite.
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