Phorbol ester-mediated suppression of cytochrome P450 Cyp1a-1 induction in murine skin: involvement of protein kinase C

Biochem Biophys Res Commun. 1992 Jul 31;186(2):970-6. doi: 10.1016/0006-291x(92)90841-8.

Abstract

Epidermal 7-ethoxyresorufin O-deethylase (EROD) activity was elevated greater than 100-fold within 4 to 7 h of topical treatment of SENCAR mice with 100 nmol dibenz[a,c]anthracene (DB[a,c]A). Treatment of skin with 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) 2 to 8 h prior to DB[a,c]A application suppressed induction by 80%. Suppression was dose-dependent over the range of 0.01 to 5 micrograms TPA (ID50 approximately 0.6 nmol). EROD activities in normal and TPA-treated epidermis paralleled steady state P450 CYP1A1 mRNA content. Analogs of TPA incapable of activating or down-regulating protein kinase C (PKC) did not suppress induction. Pretreatment of skin with sn-1,2-didecanoylglycerol, an activator of PKC which causes translocation but no down-regulation, did not suppress EROD induction. However, induction was suppressed by chrysarobin, an anthralin analog that causes PKC down-regulation in the absence of prior activation. These studies suggest that PKC participates in the processes associated with Cyp1a-1 induction and that TPA effects Cyp1a-1 induction through its down-regulation of PKC.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetone / pharmacology
  • Animals
  • Anthracenes / pharmacology
  • Benz(a)Anthracenes / pharmacology
  • Carcinogens / pharmacology
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Diglycerides / pharmacology
  • Enzyme Induction
  • Female
  • Mice
  • Mice, Inbred Strains
  • Oxidoreductases / biosynthesis*
  • Oxidoreductases / metabolism
  • Protein Kinase C / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin / enzymology*
  • Tetradecanoylphorbol Acetate / pharmacology*

Substances

  • Anthracenes
  • Benz(a)Anthracenes
  • Carcinogens
  • Diglycerides
  • RNA, Messenger
  • Acetone
  • 1,2-didecanoylglycerol
  • chrysarobin
  • Cytochrome P-450 Enzyme System
  • benz(a)anthracene
  • Oxidoreductases
  • Cytochrome P-450 CYP1A1
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate