DIFFERENTIAL-EFFECTS OF CHROMIUM(VI) ON CONSTITUTIVE AND INDUCIBLE GENE-EXPRESSION IN CHICK-EMBRYO LIVER INVIVO AND CORRELATION WITH CHROMIUM(VI)-INDUCED DNA DAMAGE
DIFFERENTIAL-EFFECTS OF CHROMIUM(VI) ON CONSTITUTIVE AND INDUCIBLE GENE-EXPRESSION IN CHICK-EMBRYO LIVER INVIVO AND CORRELATION WITH CHROMIUM(VI)-INDUCED DNA DAMAGE
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DOI：
10.1002/mc.2940020508
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发表时间：
1989-01-01
影响因子：
4.6
通讯作者：
WETTERHAHN, KE
中科院分区：
文献类型：
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作者：
HAMILTON, JW;WETTERHAHN, KE
本文研究了致癌物铬（VI）对鸡胚肝DNA的损伤对DNA作为组成型和诱导型基因转录模板功能的影响。基因表达的变化，确定使用溶液杂交和北方印迹分析，以测量稳态mRNA水平和核径流测定，以测量基因转录率，进行了比较，铬-DNA结合和铬（VI）诱导的DNA损伤，如先前测量的DNA碱性洗脱。铬（VI）处理对白蛋白、伴白蛋白（禽类转铁蛋白）或β-谷氨酰胺转铁蛋白的组成型表达基因的稳态mRNA水平或转录速率几乎没有影响或没有影响。肌动蛋白。与此相反，铬（VI）治疗有显着的，但相反的基础和药物诱导的5-氨基乙酰丙酸合成酶和细胞色素PB 1 P450的表达的影响。这两个诱导基因稳态表达的变化与转录速率的变化相似，表明铬的影响主要是转录的。铬（VI）处理增加了基础表达的两个诱导基因的4 - 5倍，在最大的，这种效果的时间过程是类似的铬（VI）诱导的DNA损伤和修复的时间过程。相比之下，铬（VI）预处理抑制了60-70%，在最大的随后诱导这些基因的谷乙米特，苯巴比妥类似物，这种效果的时间过程也对应于铬（VI）诱导的DNA损伤和修复。这些基因的表达变化的时间过程是双峰，与第二个峰值密切对应的铬（VI）诱导的DNA交联。然而，第一个峰值发生在一段时间内，当没有DNA交联或链断裂检测碱性洗脱，虽然显着水平的铬结合到DNA。这表明，铬（VI），如顺铂，最初可能会产生一个DNA单加合物，随后导致DNA交联的形成，这两种类型的铬（VI）诱导的病变有一个显着的影响靶基因的表达。
The effect of DNA damage induced by the carcinogen chromium(VI) on the function of DNA as a template for transcription of constitutive and inducible genes was examined in chick embryo liver in vivo. Changes in gene expression, determined using solution hybridization and northern blot analyses to measure steady-state mRNA levels and a nuclear run-off assay to measure gene transcription rates, were compared to chromium-DNA binding and to chromium(VI)-induced DNA damage as previously measured by DNA alkaline elution. Chromium(VI) treatment had litle or no effect on either the steady-state mRNA levels or the transcription rates of the constitutively expressed genes for albumin, conalbumin (avian transferrin), or .beta.-actin. In contrast, chromium(VI) treatment had significant but opposite effects on the basal and drug-inducible expression of 5-aminolevulinate synthase and cytochrome PB1 P450. The changes in steady-state expression of these two inducible genes were similar to the changes in transcription rate, indicating that the effects of chromium were principally transcriptional. Chromium(VI) treatment increased the basal expression of both inducible genes four- to fivefold at maximum, and the time course of this effect was similar to the time course for chromium(VI)-induced DNA damage and repair. In contrast, chromium(VI) pretreatment suppressed by 60-70% at maximum the subsequent induction of these genes by glutethimide, a phenobarbital analog, and the time course of this effect also corresponded to that of chromium(VI)-induced DNA damage and repair. The time courses of the changes in expression of these genes were bimodal, with the second peak corresponding closely to that of chromium(VI)-induced DNA cross-links. However, the first peak occurred during a period when no DNA cross-links or strand breaks were detectable by alkaline elution, although significant levels of chromium were bound to DNA. This suggests that chromium(VI), like cisplatin, may initially produce a DNA monoadduct that subsequently leads to DNA cross-link formation and that both types of chromium(VI)-induced lesions have a significant effect on the expression of targeted genes.