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Pietsch EC Hurley AL Scott EE Duckworth BP Welker ME Leone-Kabler S Townsend AJ Torti FM Torti SV 《Biochemical pharmacology》2003,65(8):1261-1269
Compounds that induce the synthesis of cytoprotective phase II enzymes have shown promise as cancer chemopreventive agents. Although chemically diverse, phase II enzyme inducers are capable of participating in Michael reaction chemistry. We have synthesized a novel class of organosulfur compounds, termed oxathiolene oxides (OTEOs). Based on their chemical properties, we hypothesized that these compounds could function as phase II enzyme inducers. Northern blot analysis showed that oxathiolene oxides induce the phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and ferritin H and L mRNA in a concentration-dependent fashion in a normal embryonic mouse liver cell line, BNLCL.2. OTEO-562 (3-cyclohexenyl-4-methyl-1,2-oxathiol-3-ene-2-oxide) was the strongest inducer. Western blot analysis demonstrated that GST-alpha and ferritin H protein levels were also induced in cells treated with OTEO-562, as was total GST and NQO1 enzyme activity. Further, induction of NQO1 activity by OTEO-562 was equivalent in aromatic hydrocarbon (Ah) receptor wild-type and Ah receptor mutant cell lines, suggesting that oxathiolene oxides activate phase II enzymes by an Ah receptor-independent mechanism. Consistent with this observation, OTEO-562 failed to induce cytochrome P450 1A1 mRNA. These results suggest that oxathiolene oxides may merit further investigation as candidate chemopreventive agents. 相似文献
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Kristen A. Mitchell 《Biochemical pharmacology》2009,77(6):947-135
The aryl hydrocarbon receptor (AhR) was implicated as a mediator of xenobiotic toxicity over three decades ago. Although a complete picture continues to elude us, investigations by many laboratories during the ensuing period have revealed much about AhR biology in normal physiological processes, as well as the toxicities induced by the dioxins and related polychlorinated aromatic hydrocarbons. The findings are captured in numerous excellent reviews. This commentary attempts to inject a new perspective on some new as well as frequently overlooked observations in the context of established receptor properties. Specifically, we examine the impact of transient versus sustained receptor activation on AhR biology, and explore the potential role for cytochrome P450 expression in regulating AhR activity amongst various tissues. The growing recognition that AhR action functions through multiple mechanisms serves to further highlight the importance of limiting prolonged receptor activation. 相似文献
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Dioxins are known to cause several human cancers through activation of the aryl hydrocarbon receptor (AhR). Harmaline and harmalol are dihydro-β-carboline compounds present in several medicinal plants such as Peganum harmala. We have previously demonstrated the ability of P. harmala extract to inhibit TCDD-mediated induction of Cyp1a1 in murine hepatoma Hepa 1c1c7 cells. Therefore, the aim of this study is to examine the effect of harmaline and its main metabolite, harmalol, on dioxin-mediated induction of CYP1A1 in human hepatoma HepG2 cells. Our results showed that harmaline and harmalol at concentrations of (0.5-12.5μM) significantly inhibited the dioxin-induced CYP1A1 at mRNA, protein and activity levels in a concentration-dependent manner. The role of AhR was determined by the inhibition of the TCDD-mediated induction of AhR-dependent luciferase activity and the AhR/ARNT/XRE formation by both harmaline and harmalol. In addition, harmaline significantly displaced [(3)H]TCDD in the competitive ligand binding assay. At posttranslational level, both harmaline and harmalol decreased the protein stability of CYP1A1, suggesting that posttranslational modifications are involved. Moreover, the posttranslational modifications of harmaline and harmalol involve ubiquitin-proteasomal pathway and direct inhibitory effects of both compounds on CYP1A1 enzyme. These data suggest that harmaline and harmalol are promising agents for preventing dioxin-mediated effects. 相似文献
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Annalisa Nannelli Francesco Rossignolo Roberto Tolando Paolo Rossato Vincenzo Longo P. Giovanni Gervasi 《Toxicology》2009
The constitutive and inducible expression of aryl hydrocarbon receptor (AhR) and of the AhR-regulated genes coding for CYP1A1, CYP1A2, CYP1B1, CYP2S1, and Nrf2 was investigated by real-time or traditional PCR in cerebral areas (cortex, cerebellum, midbrain, and hippocampus), blood–brain interfaces (meninges and brain microvessels) and liver obtained from control pigs and from pigs treated with β-naphthoflavone (βNF), a potent AhR agonist. The enzymatic activities of ethoxyresorufin-O-deethylase (EROD), and methoxyresorufin-O-deethylase (MEROD), marker for CYP1A1 and CYP1A2, the GST and various antioxidant enzymes (catalase, superoxide dismutase, GSSG-reductase, and GSH-peroxidase) were also determined in the same CNS regions. The AhR, CYP1A1, CYP1A2, CYP1B1, Nrf2 mRNAs were detected, although at different extent, in all the CNS regions, while CYP2S1 mRNA was detected only in midbrain. In the blood–brain interfaces, the constitutive basal expression of AhR and CYP1A1 was comparable to the hepatic one and even higher for CYP1B1 and Nrf2. The treatment with βNF determined the induction of CYP1A1 and 1B1 (but not of AhR, CYP1A2, and Nrf2) mRNA levels in various CNS areas; notably, CYP1A1 mRNA was increased to about 300-fold in the microvessels. The analysis of enzymatic activities revealed that EROD, but not MEROD, was induced in microsomes but not in mitochondria of all the CNS areas. However, the mitochondrial EROD activities were comparable (in midbrain, meninges) or higher (in cortex, cerebellum, hippocampus) than the microsomal ones, suggesting an important metabolic function of CYP1A1 in this subcellular localization. The activities of GST and antioxidant enzymes were detected in all CNS tissues, with levels lower than the hepatic ones, but found quite evenly distributed and marginally affected by βNF treatment. The high expression of metabolic enzymes found in blood–brain interfaces could represent a very important defence toward toxins of CNS. 相似文献
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