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Anwar Mohamed Louisville

Abstract: Anwar Mohamed Louisville

  Anwar Gamal Mohamed realized that We recently reported that vanadium (V5+) was able to decrease the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-
mediated induction of Cyp1a1 and Nqo1 at mRNA, protein and catalytic activity levels in mouse hepatoma Hepa 1c1c7
and human hepatoma HepG2 cells. However, little is known regarding the
in vivo effects. Thus, the objective of this study
was to investigate whether similar effects would occur at the
in vivo level. Therefore, we examined the effect of exposure
to V
5+ (5 mg kg1) with or without TCDD (15 mg kg1) on the AhR-regulated genes in kidney, lung and heart of C57BL/6 J
mice. Our results demonstrated that V
5+ alone significantly decreased Cyp1b1 protein and catalytic activity levels in kidney
at 24 h. Moreover, it signi
ficantly potentiated Nqo1 and Gsta1 gene expression in the heart, and only Gsta1 gene expression
in the lung. Upon co-exposure, we found that V
5+significantly inhibited the TCDD-mediated induction of Cyp1a1, Cyp1a2 and
Cyp1b1 mRNA, protein and catalytic activity levels in the kidney at 24 h. On the other hand, V
5+ significantly potentiated the
TCDD-mediated induction of Nqo1 and Gsta1 protein and activity levels in the kidney. Cyp1a1, Cyp1b1, Nqo1 mRNA, protein
and catalytic activity levels in the lung were signi
ficantly potentiated at 6 h.



Anwar Gamal Mohamed research shows that Polyhalogenated aromatic hydrocarbons, including dioxins and
dioxin-like polychlorinated biphenyls, induce a wide variety of
effects in mammals, birds and fish such as immunotoxicity,
carcinogenicity and metabolic changes. These compounds bind
to an intracellular receptor, known as the aryl hydrocarbon
receptor (AhR) (Sonneveld et al., 2007). AhR is a ligand-activated
cytoplasmic transcription factor that belongs to the basic-helixloop-helix protein family (Nebert et al., 1984). In the absence of a
ligand, AhR is associated with 90 kDa heat shock protein-90
(HSP90), the 23 kDa heat shock protein (p23) and hepatitis B virus
X-associated protein 2 (XAP2). Following ligand binding, AhR
translocates to the nucleus, dissociates from the complex, and
forms a heterodimer with the AhR nuclear translocator (Hankinson,
1995). The whole complex then acts as a transcription factor that
binds to a specific DNA recognition sequence, termed the
xenobiotic responsive element, located in the promoter region of
a number of AhR-regulated genes. Among the AhR-regulated
genes are those encoding a number of xenbiotic metabolizing
[NAD(P)H: quinone oxidoreductase-1 (NQO1), glutathione-Stransferase A1 (GSTA1), cytosolic aldehyde dehydrogenase-3
and UDP-glucuronosyltransferase 1A6 (UGT1A6) (Nebert and
Duffy, 1997; Rivera et al., 2002).
Phase I reactions include oxidation, reduction, hydrolysis,
cyclization and decyclization. If the metabolites of phase I
reactions are sufficiently polar, they may be excreted. However,
many phase I products are not eliminated rapidly and can
undergo a subsequent reaction. Several AhR ligands are not only
agonists of AhR, but also substrates for the induced phase I
enzymes with the exception of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD). The conversion of these AhR ligands into diol epoxide
compounds by CYP1A1 and CYP1A2 results in the formation of
covalent adducts when these genotoxic metabolites react with
guanines in critical genes, potentially initiating tumorigenesis
and other toxic responses (Spink et al., 2002). It is well known that
the induction of phase II enzymes serves as a detoxification
mechanism for many mutagens, carcinogens and other toxic
compounds; these are phase II reactions, usually known as
conjugation reactions, where an endogenous substrate combines
with the newly incorporated functional group to form a highly
polar conjugate. The coupling of phase II enzymes such as NQO1


and GSTA1 to these phase I enzymes is necessary to detoxify the
generated toxic metabolites prior to their excretion (Nebert and
Dalton, 2006).
Vanadium (V5+) is a poorly understood trace element that has
become a subject of interest among scientists since environ
mental contamination by V5+ has dramatically increased. This
has occurred especially in the most developed countries owing
to the widespread use of fossil fuels, many of which liberate fine
particulates of V5+ to the atmosphere during combustion (Baran,
2008). Although many biochemical and physiological functions
have been suggested for this element, V5+ still does not have a
well-known role in the higher forms of life (Baran, 2008). In vitro
and in vivo studies have demonstrated that V5+ compounds
exert protective effects against chemical-induced carcinogen
esis, mainly through modifying various xenobiotic metabo
lizing enzymes (Evangelou, 2002). Yet, it has been seen
that high V5+ concentrations are found in tissue samples of
actual tumors as compared with those in normal tissues
(Evangelou, 2002).



According to Anwar Gamal Mohamed ;


TRIzol reagent was purchased from Invitrogen (Carlsbad, CA,
USA). A high-capacity cDNA reverse transcription kit, SYBR Green
SuperMix and 96-well optical reaction plates with optical
adhesive films were purchased from Applied Biosystems (Foster
City, CA, USA). Real-time PCR primers were synthesized by
Integrated DNA Technologies Inc. 1-Chloro-2,4-dinitrobenzene,
2,6-dichlorophenolindophenol, 7-ethoxyresorufin, 7-methoxy
resorufin, anti-goat IgG peroxidase secondary antibody, dicoumarol, protease inhibitor cocktail and ammonium metavanadate
(NH4VO3) were purchased from Sigma Chemical Co. (St Louis,
MO, USA). TCDD, >99% pure, was purchased from Cambridge
Isotope Laboratories (Woburn, MA, USA). Chemilumine scence
western blotting detection reagents were from GE Healthcar

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