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Anwar-Gamal-Mohamed-Frankfort , Anwar Mohamed Frankfort

 Abstract : Anwar Gamal Mohamed Frankfort

According to Anwar Gamal Mohamed Frankfort  Acute arsenic (As(III)) exposure has been reported to cause cardiac toxicity, however this toxicity was never linked to the
disturbance in cytochrome P450 (P450)-mediated arachidonic acid metabolism. Therefore, we investigated the effect of
acute As(III) toxicity on the ex
pression of P450 and soluble epoxide hydrolase (sEH) and their associated arachidonic acid
metabolism in mice hearts. As(III) toxicity was induced by a single intraperitoneal injection of 12.5 mg/kg of As(III). Our results
showed that As(III) treatment caused a signifcant induction of the cardiac hypertrophic markers in addition to Cyp1b1, Cyp2b,
Cyp2c, Cyp4f, and sEH gene ex
pression in mice hearts. Furthermore, As(III) increased sEH protein expression and activity in
hearts with a consequent decrease in 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) formation. Whereas the formation
of 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acids (DHETs) was signifcantly increased. As(III) also increased sEH mRNA and
protein ex
pression levels in addition to the hypertrophic markers which was reversed by knockdown of sEH in H9c2 cells.
In conclusion, acute As(III) toxicity alters the ex
pression of several P450s and sEH enzymes with a consequent decrease
in the cardioprotective EETs which may represent a novel mechanism by which As(III) causes progressive cardiotoxicity.
Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent As(III)-induced hypertrophy.


About: Dr. Anwar Gamal Mohamed Frankfort  

Keywords: Cytochrome P450s, arachidonic acid metabolism, arsenic, soluble epoxide hydrolase, cardiac
hypertrophy, epoxyeicosatrienoic acids, dihydroxyeicosatrienoic acids, epoxygenases, hydroxylases


Anwar Gamal Mohamed Frankfort  realized that  Arsenic is ubiquitous in the environment, and a consid
erable percentage of the global population is su
from arsenic related organ dysfunctions because of this
unavoidable exposure (Ghosh et al. 2009). Te absorption
of both inorganic trivalent (arsenite, As(III)) and pen
tavalent (arsenate, As(V)) in the gastrointestinal tract is
high in both humans and experimental animals (Anwar
Mohamed and El-Kadi 2010). However, it has been well
documented that As(III) is far more toxic than As(V) (Cui
et al. 2008). As(III) toxicity has received increasing atten
tion as human exposure to arsenic was associated with
cardiac toxicities (Kumazaki et al. 2011; Rahman et al.
2009; Mathews et al. 2006; Patel and Kalia 2010). In addi
tion, cardiotoxicity is currently the major limitation to
the wide spread use of arsenic trioxide as an anti-cancer
medication in relapsed or refractory acute promleocytic
leukaemia (Patel et al. 2006). In general, As(III) induced
toxic e
ects are mainly attributed to the induction of oxi
dative stress and apoptosis (Zhao et al. 2008). As such,
As(III)-induced cardiotoxic e
ects include QT prolon
gation, myocardial damage, heart failure, and cardiac
arrest (Patel et al. 2006). Despite these reported As(III)-
mediated cardiotoxic e
ects, the mechanisms behind
these toxic e
ects are yet to be determined.

Anwar Gamal Mohamed Frankfort realized that Previous reports

have shown that As(III) is capable
of altering the expression of several cytochrome P450
enzymes (P450) (Davey et al. 2008; Manimaran et al.
2010; Wu et al. 2009; Ramanathan et al. 2003). However,
none of these studies investigated the e
ects of As(III)
on cardiac P450s and the subsequent e
ect on P450

mediated arachidonic acid metabolism in the heart.
Te importance of P450 enzymes in the cardiovascular
physiology emerges from their ability to metabolize
arachidonic acid to epoxyeicosatrienoic acids (EETs)
and hydroxyeicosatetraenoic acids (HETEs) (Roman
2002). Te cardioprotective e
ects of EETs has been
demonstrated in ischemia-reperfusion injury (Seubert
et al. 2007), cardiac hypertrophy (Xu et al. 2006), and
recently in As(III)-induced cardiotoxicity (Liu et al.
2011). On the other hand, 20-HETE is known to have
detrimental e
ects in many cardiovascular diseases
(Chabova et al. 2007; Lv et al. 2008; Minuz et al., 2008).
Terefore, intricate homeostatic mechanisms are
needed to keep the balance between these metabolites.
In this context, previous reports from our lab have
shown that isoproterenol-induced hypertrophy and
doxorubicin-induced cardiotoxicity disturb this balance
with decreased formation of the cardioprotective EETs
(Zordoky et al. 2008; Zordoky et al. 2010). Terefore, it
is plausible to expect that As(III)-induced cardiotoxicity
is associated with a similar disturbance to the P450-
mediated arachidonic acid metabolism.
In addition to P450 enzymes, soluble epoxide hydro
lase (sEH) is another major player in determining the
level of EETs. Te cardioprotective EETs are hydrolyzed
by sEH to the less biologically active dihydroxyeicosa
trienoic acids (DHETs) (Imig et al. 2002).
EPHX2, the
gene encoding sEH, has been found to be a susceptibility
factor for heart failure (Monti et al. 2008). In addition,
EPHX2 gene expression has been reported to increase
in animal models of angiotensin II- and isoproterenol
induced cardiac hypertrophy (Ai et al. 2009; Zordoky
et al. 2008). Moreover, sEH inhibitors have been shown
to prevent and/or reverse the development of cardiac
hypertrophy in several models (Xu et al. 2006; Loch et al.
2007; Ai et al. 2009).
Terefore, in the current study, we hypothesize
that acute As(III) cardiotoxicity alters the expression
of several P450 and sEH enzymes in the heart of male
C57Bl/6 mice. Terefore, we investigated the e
ect of
acute As(III) cardiotoxicity on the expression of several
P450 and sEH enzymes in addition to the formation of
arachidonic acid metabolites to determine whether the
changes in P450 and sEH expression have led to changes
in P450-mediated arachidonic acid metabolites. Our
fndings show that As(III)-induced cardiotoxicity causes
induction of several
P450 and EPHX2 gene expres
sions. In addition, our results provide the frst evidence
that As(III)-induced cardiotoxicity is associated with
alteration in cardiac P450-mediated arachidonic acid

Materials and methods


Anwar Gamal Mohamed Frankfort  research shows that 

High-Capacity cDNA Reverse Transcription Kit, SYBR
Green SuperMix, and 96-well optical reaction plates
with optical adhesive flms, rat sEH (EPHX2) Silencer
Select Pre-designed and validated siRNA, and Silencer®
Select Negative Control #2 siRNA were purchased
from Applied Biosystems (Foster City, CA). Real time
PCR primers were synthesized by Integrated DNA
Technologies Inc. (San Diego, CA) according to previ
ously published sequences. Arachidonic acid, 4-hydroxy
benzophenone, and sodium arsenite were purchased
from Sigma-Aldrich (St. Louis, MO).


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