Quinone methide mediates in vitro induction of ornithine decarboxylase by the tumor promoter butylated hydroxytoluene hydroperoxide.
Quinone methide mediates in vitro induction of ornithine decarboxylase by the tumor promoter butylated hydroxytoluene hydroperoxide.
复制标题
醌甲基化物通过肿瘤促进剂丁基化羟基甲苯氢过氧化物在体外介导鸟氨酸脱羧酶。
DOI：
10.1093/carcin/15.5.817
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发表时间：
1994
期刊：
影响因子：
4.7
通讯作者：
Kensler,TW
中科院分区：
文献类型：
--
作者：
Guyton,KZ;Dolan,PM;Kensler,TW
皮肤肿瘤促进剂丁基羟基甲苯过氧化氢((2，6-di-tert-butyl-4-hydroperoxyl-4-methyl-2，5-cyclohexadienone；)代谢成活性中间体是该化合物促进肿瘤发生所必需的。特别是，已知一种亲电性的苯醌甲醚可介导BHTOOH对人活体肿瘤的促进作用以及体外细胞毒性。在本研究中，我们研究了这种活性中间体在角质形成细胞中诱导鸟氨酸脱羧酶(ODC)的作用，ODC是一种与肿瘤发生密切相关的基因。BHTOOH刺激ODC酶活性的时间依赖性增加，与ODC mRNA的诱导平行，提示BHTOOH对ODC的转录调控。细胞内谷胱甘肽的耗竭导致角质形成细胞对BHTOOH的敏感性增加5倍。同样，BHTOOH诱导的ODC可被可溶性硫醇化合物完全抑制。这些结果表明，ODC的诱导是由BHTOOH的硫醇反应性代谢产物介导的。铁特异的螯合剂Desferal阻断了BHTOOH诱导的ODC，表明该中间体的形成是铁依赖的。BHTOOH的4-甲基被逐渐增大的烷基取代可相应地减少苯醌甲烷的产生；对这些BHTOOH类似物的比较研究表明，对ODC的诱导效力相应地丧失，表明BHT-QQ甲基介导了BHTOOH对ODC的体外诱导。最后，激酶抑制剂研究表明，蛋白激酶C在BHTOOH诱导ODC的过程中发挥了作用。综上所述，这些结果为深入了解反应性电泳性BHT-QQ甲基可以介导基因表达变化的细胞机制提供了洞察力，例如在体内肿瘤促进中发生的变化。
Metabolism of the skin tumor promoter butylated hydroxy-toluene hydroperoxide (2,6-di-tert-butyl-4-hydroperoxyl-4-methyl-2,5-cyclohexadienone; BHTOOH) to reactive intermediates is required for tumor promotion by this compound. In particular, an electrophilic quinone methide is known to mediate bothin vivotumor promotion as well asin vitrocytotoxicity by BHTOOH. In the present study, the role of this reactive intermediate in the induction of ornithine de-carboxylase (ODC), a gene strongly associated with tumor promotion, was investigated in cultured keratinocytes. BHTOOH stimulates a time-dependent increase in ODC enzyme activity, paralleled by ODC mRNA induction, suggesting transcriptional regulation of ODC by BHTOOH. Depletion of intracellular glutathione caused a 5-fold potentiation of keratinocyte sensitivity to BHTOOH. Concordantly, ODC induction by BHTOOH could be completely inhibited by soluble thiol compounds. These results suggest that ODC induction is mediated by a thiol-reactive metabolite of BHTOOH. The iron-specific chelator desferal blocked ODC induction by BHTOOH, indicating that formation of this intermediate is iron-dependent. Substitution of the 4-methyl group of BHTOOH with alkyl groups of incrementally larger size is known to reduce accordingly quinone methide production; comparative study of these BHTOOH analogs demonstrated a corresponding loss of potency for ODC induction, indicating that BHT-quinone methide mediates thein vitroinduction of ODC by BHTOOH. Finally, kinase inhibitor studies suggested a role for protein kinase C in the induction of ODC by BHTOOH. Taken together, these results provide insight into the cellular mechanisms through which the reactive electrophile BHT-quinone methide can mediate alterations in gene expression, such as occur in tumor promotionin vivo.