Coinduction of multiple hepatic cytochrome P-450 proteins and their mRNAs in rats treated with imidazole antimycotic agents.
Coinduction of multiple hepatic cytochrome P-450 proteins and their mRNAs in rats treated with imidazole antimycotic agents.
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发表时间：
1989-03
影响因子：
3.6
通讯作者：
K. Hostetler;S. Wrighton;D. Molowa;P. Thomas;W. Levin;P. Guzelian
中科院分区：
文献类型：
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作者：
K. Hostetler;S. Wrighton;D. Molowa;P. Thomas;W. Levin;P. Guzelian
为了描述咪唑类抗真菌药物增加细胞色素P-450的分子基础，我们研究了用克霉唑、咪康唑或酮康唑治疗雌性大鼠对主要诱导型肝细胞色素P-450 （P-450p、P-450b/e、P-450c/d和P-450j）表达的影响。通过测量肝微粒体中免疫反应性细胞色素P-450的含量，以及与克隆的P-450 cdna杂交的肝脏RNA的数量，我们确定糖皮质激素反应性P-450p主要是由克霉唑、咪康唑和酮康唑诱导的，比对照值高出382倍。氯霉唑和咪康唑对苯巴比妥反应性细胞色素P-450b/e也有较强的诱导作用，但酮康唑对其无诱导作用。三种抗真菌药物均可适度提高芳香烃诱导的细胞色素P-450c/d，而酮康唑对乙醇反应性细胞色素P-450j有轻微的诱导作用，而克霉唑和咪康唑则没有。在某些情况下，但不是所有情况下，用抗真菌药物治疗大鼠导致P-450蛋白的积累显著超过相应P-450 mRNA的增加。综上所述，咪唑类抗真菌药物通过P-450 mRNA和蛋白积累的不同机制，对大鼠肝细胞色素P-450至少四个不同基因亚家族的表达进行了差异调节。
To characterize the molecular basis by which imidazole antimycotic drugs increase cytochrome P-450, we examined the effects of treating female rats with clotrimazole, miconazole, or ketoconazole on expression of the major inducible forms of hepatic cytochromes P-450 (P-450p, P-450b/e, P-450c/d, and P-450j). From measurements of the content of immunoreactive cytochromes P-450 in liver microsomes and of the amounts of liver RNA hybridizing to cloned P-450 cDNAs, we established that the glucocorticoid-responsive P-450p is the form predominantly induced by clotrimazole, miconazole, and ketoconazole, to as much as 382 times above control values. The phenobarbital-responsive cytochromes P-450b/e were also induced strongly by clotrimazole and miconazole, but not by ketoconazole. Aromatic hydrocarbon-inducible cytochromes P-450c/d were modestly elevated by each of these three antifungal drugs whereas ethanol-responsive P-450j was marginally induced by ketoconazole, but not by clotrimazole or miconazole. In some, but not all cases, treatment of rats with antifungal drugs resulted in accumulation of P-450 protein that significantly exceeded the increase in the corresponding P-450 mRNA. In conclusion, imidazole antifungal drugs differentially modulate the expression of at least four distinct gene subfamilies of rat hepatic cytochrome P-450 by separate mechanisms involving accumulation of P-450 mRNA and protein.