Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole.
Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole.
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通过色氨酸衍生的 6-甲酰基吲哚并[3,2-b]咔唑的代谢调节 CYP1A1 转录。
DOI：
10.1006/abbi.2000.2037
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发表时间：
2000
影响因子：
3.9
通讯作者：
A. Rannug
中科院分区：
文献类型：
--
作者：
Yu;Yu;Linda Bergander;U. Rannug;A. Rannug
细胞色素P4501 A1（CYP 1A 1）酶在小鼠肝癌细胞中具有代谢内源性底物和自身转录调节的功能。在本研究中，6-甲酰吲哚并[3，2-B]咔唑（FICZ），一个建议的内源性配体的芳烃受体（AhR），已在小鼠Hepa-1细胞系中的细胞色素P450 1A 1基因转录的调节进行了研究。色氨酸的光产物，FICZ，先前已被表征为具有非常高的AhR结合亲和力，并在皮摩尔浓度下瞬时诱导培养细胞中的CYP 1A 1基因表达。本研究的结果表明，仅在野生型细胞中观察到低浓度FICZ对CYP 1A 1 mRNA的瞬时诱导。在c37细胞中，缺乏CYP 1A 1，FICZ引起持续的诱导。有趣的是，我们发现培养基中较高量的色氨酸增加了c37细胞中CYP 1A 1 mRNA表达的组成性水平，但在野生型细胞中没有。这表明培养基中的一种来源于Escherichan的AhR配体调节基础CYP 1A 1表达。在使用由c37细胞制备的S9进行的代谢研究中，FICZ未形成代谢产物，也未观察到FICZ损失，而野生型细胞FICZ代谢迅速。HPLC分析显示，当与大鼠肝S9孵育时，FICZ以NADPH依赖性方式形成至少三种代谢产物。CYP 1A 1抑制剂椭圆藤碱完全阻断FICZ的代谢。椭圆藤碱还增强了基础和FICZ诱导的CYP 1A 1 mRNA表达。总之，这些结果表明，色氨酸是内源性配体的前体，并且建议的色氨酸衍生配体FICZ是CYP 1A 1酶的底物，并且参与CYP 1A 1转录的自动调节。
A functional cytochrome P4501A1 (CYP1A1) enzyme has been suggested to metabolize endogenous substrates and to autoregulate its own transcription in mouse hepatoma cells. In the present study, the regulation of CYP1A1 gene transcription by 6-formylindolo[3,2-b]carbazole (FICZ), a suggested endogenous ligand for the aryl hydrocarbon receptor (AhR), has been studied in mouse Hepa-1 cell lines. The tryptophan photoproduct, FICZ, has previously been characterized to possess very high AhR binding affinity and to transiently induce CYP1A1 gene expression in cultured cells at picomolar concentrations. The results from this study show that a transient induction of CYP1A1 mRNA at a low concentration of FICZ was only seen in wild-type cells. In c37 cells, deficient in CYP1A1, FICZ caused a sustained induction. Interestingly, we found that a higher amount of tryptophan in culture medium increased the constitutive level of CYP1A1 mRNA expression in the c37 cells but not in the wild-type cells. This suggests that a tryptophan-derived AhR ligand in the medium regulates the basal CYP1A1 expression. In metabolism studies performed with S9 prepared from c37 cells no metabolites were formed from FICZ and no loss of FICZ was observed, while with wild-type cells FICZ was rapidly metabolized. HPLC analysis revealed that at least three metabolites were formed in an NADPH-dependent manner from FICZ when incubated with rat liver S9. The CYP1A1 inhibitor ellipticine totally blocked the metabolism of FICZ. Ellipticine also enhanced both basal and FICZ-induced CYP1A1 mRNA expression. Taken together, these results indicate that tryptophan is a precursor of the endogenous ligand and that the suggested tryptophan-derived ligand FICZ is a substrate for the CYP1A1 enzyme and is involved in autoregulation of CYP1A1 transcription.
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影响因子：
5.8
作者：
NEBERT, DW
通讯作者：
NEBERT, DW
DOI：
--
发表时间：
2000-02
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
B. Moorthy;K. M. Parker;Charles V. Smith;J. Bend;S. Welty
通讯作者：
B. Moorthy;K. M. Parker;Charles V. Smith;J. Bend;S. Welty
功能性 CYP1A1 和 CYP1A2 蛋白对小鼠胞质醛脱氢酶 3 (Aldh-3c) 基因的负调控。
DOI：
10.1016/s0006-291x(05)81508-6
发表时间：
1992
影响因子：
3.1
作者：
Vasiliou,V;Puga,A;Nebert,DW
通讯作者：
Nebert,DW
使用人工智能研究 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 受体配体的结构亲和力相关性。
影响因子：
4.7
作者：
Rannug,U;Sjögren,M;Rannug,A;Gillner,M;Toftgård,R;Gustafsson,JA;Rosenkranz,H;Klopman,G
通讯作者：
Klopman,G
10T1/2 细胞中基于代谢的多环芳香乙炔对 CYP1B1 的抑制可增强芳烃受体活性。
影响因子：
3.8
作者：
Alexander,DL;Zhang,L;Foroozesh,M;Alworth,WL;Jefcoate,CR
通讯作者：
Jefcoate,CR