Suppression of constitutive cytochrome P-450 gene expression in livers of rats undergoing an acute phase response to endotoxin.
Suppression of constitutive cytochrome P-450 gene expression in livers of rats undergoing an acute phase response to endotoxin.
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作者：
E. Morgan
向雄性大鼠给予纯化细菌脂多糖（LPS）可在24小时内将雄性特异性细胞色素P-450 [AH，还原黄素蛋白：氧氧化还原酶（RH羟化），E.C.1.14.14.1]同工酶P-450 h（P450 IIC 11）的组成性肝脏表达抑制至对照水平的约35%。P-450 h的mRNA比蛋白质受到更迅速和更深刻的抑制，表明（a）mRNA的减少是蛋白质受到抑制的原因，（B）其他机制在其mRNA受到抑制的情况下维持P-450 h脱辅基蛋白的表达。P-450 h表达的抑制在30-100 μ g/kg的内毒素剂量下最大，表明P-450抑制伴随着肝分泌蛋白的急性期反应。雌性特异性细胞色素P-450同工酶，P-450 i（P450 IIC 12），被抑制到对照水平的17%，通过在雌性大鼠中给予LPS。抑制P-450 i载脂蛋白的LPS，其表达的恢复，是更快的抑制P-450 h的男性。P-450 i蛋白和mRNA水平同时被LPS抑制，这表明虽然存在翻译前组分的抑制，但其他机制也可能起作用。基于未处理大鼠肝脏中P-450 h和P-450 i微粒体含量相对于总细胞色素P-450的估计值的计算表明，这些形式的抑制显著有助于LPS处理后总微粒体P-450的降低。在这些研究中，雄性和雌性大鼠的肝微粒体NADPH-细胞色素c还原酶（TPNH 2-细胞色素c还原酶，E.C.1.6.2.4）的活性和细胞色素b5的含量降低LPS给药。与其对细胞色素P-450表达的影响一样，内毒素对NADPH-细胞色素c还原酶活性和细胞色素b5水平的抑制在雌性大鼠中比雄性大鼠中更快。通过皮下注射姜黄素在雄性大鼠中产生局部炎症反应，对细胞色素P-450、P-450 h表达和细胞色素b5产生的影响与内毒素相似，但实现的速度较慢。
Administration of purified bacterial lipopolysaccharide (LPS) to male rats suppressed the constitutive hepatic expression of the male-specific cytochrome P-450 [AH, reduced flavoprotein:oxygen oxidoreductase (RH hydroxylating), E.C.1.14.14.1] isozyme P-450h (P450IIC11) to about 35% of control levels within 24 hr. The mRNA for P-450h was more rapidly and more profoundly suppressed than was the protein, indicating (a) that the decrease in the mRNA was responsible for the suppression of the protein and (b) that other mechanisms work to maintain expression of P-450h apoprotein in the face of repression of its mRNA. Suppression of P-450h expression was maximal at an endotoxin dose of 30-100 micrograms/kg, indicating that P-450 suppression is concomitant with the acute-phase response of hepatic secretory proteins. The female-specific cytochrome P-450 isozyme, P-450i (P450IIC12), was suppressed to 17% of control levels by LPS administration in female rats. Suppression of the P-450i apoprotein by LPS, and recovery of its expression, was more rapid than was suppression of P-450h in males. P-450i protein and mRNA levels were concomitantly suppressed by LPS, indicating that although there is a pretranslational component to the suppression, other mechanisms may also contribute. Calculations based on estimations of the microsomal contents of P-450h and P-450i relative to the total cytochrome P-450 in untreated rat livers indicate that suppression of these forms contributes significantly to the decreases in total microsomal P-450 after LPS treatment. In these studies, hepatic microsomal NADPH-cytochrome c reductase (TPNH2-cytochrome c reductase, E.C.1.6.2.4) activities and content of cytochrome b5 were decreased by LPS administration in both male and female rats. Like its effects on cytochrome P-450 expression, endotoxin suppression of NADPH-cytochrome c reductase activities and cytochrome b5 levels was more rapid in female rats than in males. The production of a local inflammatory response in male rats by subcutaneous injection of turpentine caused effects on cytochrome P-450, P-450h expression, and cytochrome b5 that were similar to those of endotoxin but were less rapidly achieved.