Phorbol ester-mediated suppression of cytochrome P450 Cyp1a-1 induction in murine skin: involvement of protein kinase C.
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.
Reiners
J J
JJ
Research Division University of Texas M.D. Anderson Cancer Center, Smithville 78957.
Cantu
A R
AR
Schöller
A
A
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000873:Anthracenes; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D004075:Diglycerides; D012333:RNA, Messenger; D000096:Acetone; C044297:1,2-didecanoylglycerol; C013883:chrysarobin; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate