Sherratt A J, Banet D E, Linder M W, Prough R A
Department of Biochemistry, University of Louisville School of Medicine, Kentucky.
J Pharmacol Exp Ther. 1989 May;249(2):667-72.
The potentiation of the expression of polycyclic aromatic hydrocarbon-inducible cytochromes P450IA1 and P450IA2, and phenobarbital-inducible cytochrome P450IIB1 and NADPH-cytochrome P-450 reductase by dexamethasone in vivo was investigated using adrenalectomized and sham-operated rats. Hepatic cytochrome P450IA1 activity (determined by ethoxyresorufin O-deethylase activity) was induced maximally (30-fold) in both sham-operated and adrenalectomized rats 24 hr after a single injection of 3-methylcholanthrene (10 mg/kg). Dexamethasone (10 mg/kg) increased hepatic tyrosine aminotransferase activity 3- to 4-fold, but had little or no effect on ethoxyresorufin O-deethylase activity. However, dexamethasone potentiated the 3-methylcholanthrene-dependent induction of hepatic P450IA1 activity 2- to 3-fold in adrenalectomized rats and 1.5- to 2-fold in sham-operated rats when administered concomitantly with 3-methylcholanthrene (P less than .05). The dose of dexamethasone required to potentiate 3-methylcholanthrene induction of P450IA1 activity (greater than 1 mg/kg) correlated well with the dose required to induce hepatic tyrosine aminotransferase activity; a marker of glucocorticoid action. Potentiation of 3-methylcholanthrene induction of P450IA1 activity in the rat appears to be tissue specific in that dexamethasone was found not to potentiate 3-methylcholanthrene induction of P450IA1 activity of rat lung or kidney. Cytochrome P450IA1 content induced by 3-methylcholanthrene in the liver was also potentiated 2- to 3-fold by dexamethasone. In contrast, potentiation of 3-methylcholanthrene induction of cytochrome P450IA2 content was not observed. Western blot analyses indicate that the increase in monooxygenase activity induced by 3-methylcholanthrene or 3-methylcholanthrene plus dexamethasone corresponds well only with the induction of cytochrome P450IA1 protein content.(ABSTRACT TRUNCATED AT 250 WORDS)
利用肾上腺切除大鼠和假手术大鼠，研究了地塞米松在体内对多环芳烃诱导的细胞色素P450IA1和P450IA2以及苯巴比妥诱导的细胞色素P450IIB1和NADPH - 细胞色素P - 450还原酶表达的增强作用。单次注射3 - 甲基胆蒽（10mg/kg）24小时后，假手术大鼠和肾上腺切除大鼠的肝细胞色素P450IA1活性（通过乙氧基异吩恶唑酮O - 脱乙基酶活性测定）均被最大程度诱导（30倍）。地塞米松（10mg/kg）使肝酪氨酸转氨酶活性增加3至4倍，但对乙氧基异吩恶唑酮O - 脱乙基酶活性几乎没有影响。然而，当与3 - 甲基胆蒽同时给药时，地塞米松使肾上腺切除大鼠肝P450IA1活性的3 - 甲基胆蒽依赖性诱导增强2至3倍，在假手术大鼠中增强1.5至2倍（P小于0.05）。增强P450IA1活性的3 - 甲基胆蒽诱导所需的地塞米松剂量（大于1mg/kg）与诱导肝酪氨酸转氨酶活性所需的剂量密切相关；肝酪氨酸转氨酶活性是糖皮质激素作用的一个标志物。地塞米松似乎对大鼠肺或肾的P450IA1活性的3 - 甲基胆蒽诱导没有增强作用，表明大鼠中3 - 甲基胆蒽诱导的P450IA1活性的增强具有组织特异性。地塞米松还使3 - 甲基胆蒽在肝脏中诱导的细胞色素P450IA1含量增强2至3倍。相比之下，未观察到地塞米松对3 - 甲基胆蒽诱导的细胞色素P450IA2含量的增强作用。蛋白质免疫印迹分析表明，3 - 甲基胆蒽或3 - 甲基胆蒽加地塞米松诱导的单加氧酶活性增加仅与细胞色素P450IA1蛋白含量的诱导良好对应。（摘要截短至250字）
