Salonpää P, Krause K, Pelkonen O, Raunio H
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Apr;351(4):446-52. doi: 10.1007/BF00169087.
Coumarin 7-hydroxylase (COH) activity is catalyzed by the Cyp2a-5 gene product (CYP2A5 enzyme) in mice. Mouse hepatic CYP2A5 expression is often increased in conditions in which other P450 forms are repressed, e.g. after the administration of heavy metals and other toxic agents known to affect cellular heme balance. In this study, the effect of various porphyrinogenic chemicals on the expression CYP2A5 and the key enzymes in heme metabolism was studied. Administration of single doses of griseofulvin (1000 mg/kg), thioacetamide (10 mg/kg) and aminotriazole (1000 mg/kg) to DBA/2 and C57BL/6 mice produced up to 10-fold increases in hepatic COH catalytic activity. Dramatic, up to 130-fold increases in response to the inducers was observed in the amount of CYP2A5 steady-state mRNA. The mRNA contents of aminolevulinate synthase, ferrochelatase and heme oxygenase were also increased to a variable extent, possibly reflecting feed-back regulatory mechanisms. In D2 mice the CYP2A5 inducing effect of aminotriazole and thioacetamide, but not that of griseofulvin, pyrazole and phenobarbital, was abolished by exogenously administered heme arginate. In the B6 strain heme arginate treatment increased CYP2A5 expression but it did not affect the induction caused by porphyrinogenic agents. These results show that porphyrinogenic agents act as efficient inducers of CYP2A5, and suggest that regulation of the transcription of the Cyp2a-5 gene could in some instances involve heme-sensitive factors.
香豆素7-羟化酶（COH）活性在小鼠体内由Cyp2a - 5基因产物（CYP2A5酶）催化。在其他P450形式受到抑制的情况下，如给予已知会影响细胞血红素平衡的重金属和其他有毒物质后，小鼠肝脏CYP2A5表达通常会增加。在本研究中，研究了各种致卟啉化学物质对CYP2A5表达及血红素代谢关键酶的影响。给DBA/2和C57BL/6小鼠单次注射灰黄霉素（1000 mg/kg）、硫代乙酰胺（10 mg/kg）和氨基三唑（1000 mg/kg），可使肝脏COH催化活性提高多达10倍。观察到CYP2A5稳态mRNA量对诱导剂的反应急剧增加，高达130倍。氨基乙酰丙酸合酶、亚铁螯合酶和血红素加氧酶的mRNA含量也有不同程度增加，这可能反映了反馈调节机制。在D2小鼠中，外源性给予精氨酸血红素可消除氨基三唑和硫代乙酰胺对CYP2A5的诱导作用，但灰黄霉素、吡唑和苯巴比妥的诱导作用不受影响。在B6品系中，精氨酸血红素处理增加了CYP2A5表达，但不影响致卟啉剂引起的诱导作用。这些结果表明，致卟啉剂是CYP2A5的有效诱导剂，并表明在某些情况下，Cyp2a - 5基因转录的调节可能涉及血红素敏感因子。
