# PROTEIN KINASE C REGULATION OF P-450 SYSTEM

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 1992 · $179,290

## Abstract

Treatment of murine skin and cultures of murine epidermal or
hepatoma cells with 12-0-tretradecanoylphorbol-13-acetate (TPA)
reduces basal cytochrome P450-dependent monooxygenase activities,
and suppresses the rise in the monooxygenase 7-ethoxyresorufin
O-deethylase (7-ERD) that normally occurs after treatment with P450
inducers.  TPA is a potent activator of protein kinase C (PKC).  The
overall hypothesis of the proposal is that PKC regulates the
expression/activities of some P-450 species.  This hypothesis will
be examined by analyzing the effects of PKC inhibitors and PKC down
regulation on the TPA-dependent suppression of 7-ERD induction in
the aforementioned systems.  PKC activators structurally unrelated
to TPA, and analogs of TPA incapable of activating PKC will also be
surveyed for their abilities to modulate 7-ERD (cytochrome CYPIA1)
expression.  Analyses of 7-ERD induction in cultured epidermal and
hepatoma cells will also be made following reduction or elevation
of cellular PKC activities by transfection of PKC antisense
oligodeoxynucleotides or PKC cDNA expression vectors, respectively.
Antibodies and cDNA probes to P-450IAl will be used to determine
whether the TPA-mediated effects on 7-ERD activity reflect
transcriptional or post-transcriptional regulation.  If steady state
RNA levels are affected by TPA, rates of IA1 transcription and IA1
mRNA half lifes will be determined.  Relevance of PKC mediated
suppression of IA1 induction to the processes of in vivo xenobiotic
metabolism and chemical carcinogenesis will be assessed by analyses
of epidermal DNA-adducts and the numbers of skin tumors that develop
in an initiation-promotion protocol employing benzo[a]pyrene as the
initiator.  Lastly, the effects of TPA and other PKC activators on
the inductions of P-450 cytochromes IA1, IA2, IIB1, IIB2, and IIE1
in rat liver will be determined to assess the generality of PKC as
a regulator of P450 expression.  These studies will characterize a
new and novel mechanism for the regulation of the P-450 system, and
may proyide a general explanation for the suppressive effects of a
variety ot agents on the P-450 system.

## Key facts

- **NIH application ID:** 3172181
- **Project number:** 2R01CA034469-09A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **SAM.gov UEI:** M6K6NTJ2MNE5
- **Principal Investigator:** JOHN J REINERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $179,290
- **Award type:** 2
- **Project period:** 1983-09-01 → 1995-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172181

## Citation

> US National Institutes of Health, RePORTER application 3172181, PROTEIN KINASE C REGULATION OF P-450 SYSTEM (2R01CA034469-09A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172181. Licensed CC0.

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