Transcriptional and posttranscriptional regulation of CYP1A1 by vanadium in human hepatoma HepG2 cells

Abstract

We recently demonstrated that V(5+) downregulates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of Cyp1a1 mRNA, protein, and catalytic activity levels in Hepa 1c1c7 cells through transcriptional mechanism. Therefore, it is important to investigate whether similar changes occur in humans. For this purpose, we examined the effect of V(5+) (as ammonium metavanadate, NH(4)VO(3)) on the expression of aryl hydrocarbon receptor (AhR)-regulated gene; cytochrome P450 1A1 (CYP1A1) at each step of the AhR signal transduction pathway in human hepatoma HepG2 cells. Our results show a significant reduction in TCDD-mediated induction of CYP1A1 mRNA, protein, and activity levels after V(5+) treatment in a dose-dependent manner. Investigating the effect of co-exposure to V(5+) and TCDD at transcriptional levels revealed that V(5+) significantly inhibited TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. Looking at the posttranscriptional level, V(5+) did not affect CYP1A1 mRNA stability, thus eliminating the possible role of V(5+) in modifying CYP1A1 gene expression through this mechanism. On the other hand, at the posttranslational level, V(5+) was able to significantly decrease CYP1A1 protein half-life contributing to the inconsistency between catalytic activity and transcriptional level. Importantly, we showed that V(5+) did not significantly alter the heme oxygenase-1 mRNA level, thus eliminating any possibility that V(5+) might have decreased CYP1A1 activity through affecting its heme content. This study demonstrates for the first time that V(5+) downregulates the expression of CYP1A1 at the transcriptional, posttranscriptional and posttranslational mechanisms in the human hepatoma HepG2 cells.

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

“…The data are expressed the means 6 S.D. causes a significant upregulation of CYP1A1/2 mRNAs expression [Misaki et al, 2007;Abdelhamid et al, 2010;Zhang et al, 2011]. Consistent with these results, DiMeDBC and mainly N-MeDBC increased substantially the CYP1A1/2 mRNA levels in HepG2 cells.…”

Cytochrome P4501A mRNA and protein induction in striped bass (Morone saxatilis)

“…Cytochrome P4501A is a monooxygenase involved in xenobiotic biotransformation and detoxification of many PAHs, PCBs and dioxins and is induced by the binding of these compounds with aryl hydrocarbon receptor (AhR), that is, a cytosolic ligand-activated transcription factor Hahn 2001). The induction of Cyp1a may then be regulated at various post-transcriptional steps (Abdelhamid et al 2010;Amara et al 2010). Cytochrome P4501A can also be activated by other pathways and plays a strong role in steroid hormone biosynthesis, tryptophan and retinol metabolism (review in Monostory et al 2009).…”

Modulation of aryl hydrocarbon receptor‐regulated genes by acute administration of ammonium metavanadate in kidney, lung and heart of C57BL/6 mice

“…Previous reports from our laboratory demonstrated that V 5+ was able to decrease the TCDD‐mediated induction of Cyp1a1 and Nqo1 at mRNA, protein, and catalytic activity levels in the mouse hepatoma Hepa 1c1c7 cells (Anwar‐Mohamed and El‐Kadi, ; Anwar‐Mohamed and El‐Kadi, ) and in human hepatoma HepG2 cells (Abdelhamid et al ., , ). However, it was not reported previously if V 5+ could affect TCDD‐mediated induction of Cyp1a1, Cyp1a2 and Cyp1b1 mRNA, protein or catalytic activity levels in the kidney, lung or heart of C57BL/6 mice.…”

“…Moreover, few studies have examined the combined toxicological effects of these ligands with heavy metals such as V 5+ . At the in vitro level, we recently reported that V 5+ was able to decrease the TCDD‐mediated induction of Cyp1a1 and Nqo1 at mRNA, protein and catalytic activity levels in the mouse hepatoma Hepa 1c1c7 cells, which were derived from BW7756 mouse hepatoma that arose in a C57BL/6 mouse (Anwar‐Mohamed and El‐Kadi, , ) and in human hepatoma HepG2 cells, which were derived from the liver tissue of a 15‐year‐old Caucasian American male with a well‐differentiated hepatocellular carcinoma (Abdelhamid et al ., , ). However, to the best of our knowledge, there has been no previous attempt to examine the effect of V 5+ on the regulation of AhR‐regulated genes in the presence and absence of TCDD in extrahepatic tissues in vivo .…”