Timsit Y E, Riddick D S
Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Toxicol Appl Pharmacol. 2000 Mar 1;163(2):105-14. doi: 10.1006/taap.1999.8862.
Cytochrome P450 2C11 (CYP2C11) is a sexually dimorphic liver enzyme whose expression is regulated by the male pulsatile pattern of growth hormone (GH) secretion. Hepatic CYP2C11 expression is down-regulated by polycyclic aromatic hydrocarbons such as 3-methylcholanthrene (MC). An attractive hypothesis as to the mechanism of CYP2C11 down-regulation by aromatic hydrocarbons is the disruption of normal GH signaling by exposure to these compounds. To evaluate the effects of MC on the ability of GH to stimulate hepatic CYP2C11 expression, our approach was to employ GH replacement in male Fischer 344 rats made GH-deficient by hypophysectomy (hypx). Groups of hypx rats received the following treatments: vehicle; GH alone (twice daily, 125 microg/kg sc, days 1-6); MC alone (20 mg/kg gavage, days 1, 3, and 5); and both GH and MC. Rats were euthanized on day 7. As a positive control response, pronounced induction of hepatic CYP1A1 apoprotein was observed in all MC-treated rats. CYP2C11 expression in hypx rats receiving GH alone was increased at the mRNA, apoprotein, and catalytic activity (testosterone 16alpha-hydroxylation) levels, with mRNA and apoprotein levels approaching that of intact male rats. The inability of GH to fully restore CYP2C11 catalytic activity was attributed to the lowered NADPH-cytochrome P450 reductase apoprotein and catalytic activity observed in all hypx rats. CYP2C11 expression in hypx rats receiving both GH and MC was significantly lower at the mRNA, apoprotein, and catalytic activity levels than that observed in hypx rats treated with GH alone, but significantly higher at the mRNA, apoprotein, and catalytic activity levels than that observed in vehicle-treated hypx rats and in hypx rats treated with MC alone. These data suggest that MC interferes with the ability of GH to stimulate CYP2C11 expression. Thus, disruption of GH signaling by aromatic hydrocarbons may represent a mechanism contributing to the suppression of CYP2C11 gene expression.
细胞色素P450 2C11（CYP2C11）是一种具有性别差异的肝脏酶，其表达受雄性生长激素（GH）脉冲式分泌模式的调节。肝脏CYP2C11的表达会被多环芳烃如3-甲基胆蒽（MC）下调。关于芳烃下调CYP2C11的机制，一个有吸引力的假说是这些化合物暴露会破坏正常的GH信号传导。为了评估MC对GH刺激肝脏CYP2C11表达能力的影响，我们的方法是在通过垂体切除（hypx）造成GH缺乏的雄性Fischer 344大鼠中进行GH替代。将几组hypx大鼠进行以下处理：溶剂；单独使用GH（每日两次，125μg/kg皮下注射，第1 - 6天）；单独使用MC（20mg/kg灌胃，第1、3和5天）；以及同时使用GH和MC。在第7天对大鼠实施安乐死。作为阳性对照反应，在所有接受MC处理的大鼠中均观察到肝脏CYP1A1载脂蛋白的明显诱导。单独接受GH的hypx大鼠中，CYP2C11在mRNA、载脂蛋白和催化活性（睾酮16α-羟化）水平上均增加，mRNA和载脂蛋白水平接近完整雄性大鼠。GH无法完全恢复CYP2C11催化活性归因于在所有hypx大鼠中观察到的NADPH-细胞色素P450还原酶载脂蛋白和催化活性降低。同时接受GH和MC的hypx大鼠中，CYP2C11在mRNA、载脂蛋白和催化活性水平上均显著低于单独接受GH处理的hypx大鼠，但在mRNA、载脂蛋白和催化活性水平上显著高于接受溶剂处理的hypx大鼠以及单独接受MC处理的hypx大鼠。这些数据表明MC干扰了GH刺激CYP2C11表达的能力。因此，芳烃对GH信号传导的破坏可能是导致CYP2C11基因表达受抑制的一种机制。
