Reiners J J, Cantu A R, Schöller A
Research Division University of Texas M.D. Anderson Cancer Center, Smithville 78957.
Biochem Biophys Res Commun. 1992 Jul 31;186(2):970-6. doi: 10.1016/0006-291x(92)90841-8.
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.
用100 nmol二苯并[a,c]蒽（DB[a,c]A）对SENCAR小鼠进行局部处理后4至7小时内，表皮7-乙氧基异吩恶唑酮O-脱乙基酶（EROD）活性升高超过100倍。在应用DB[a,c]A之前2至8小时，用2微克的12-O-十四烷酰佛波醇-13-乙酸酯（TPA）处理皮肤，可使诱导作用抑制80%。在0.01至5微克TPA范围内，抑制作用呈剂量依赖性（半数抑制剂量约为0.6 nmol）。正常和TPA处理的表皮中的EROD活性与稳态P450 CYP1A1 mRNA含量平行。不能激活或下调蛋白激酶C（PKC）的TPA类似物不会抑制诱导作用。用sn-1,2-二癸酰甘油（一种PKC激活剂，可导致转位但不会下调）预处理皮肤，不会抑制EROD诱导。然而，蒽林（一种在没有预先激活的情况下会导致PKC下调的蒽林类似物）可抑制诱导作用。这些研究表明，PKC参与了与Cyp1a-1诱导相关的过程，并且TPA通过其对PKC的下调作用影响Cyp1a-1诱导。
