H. Korashy - Profile on Academia.edu (original) (raw)
Papers by H. Korashy
Basic & Clinical Pharmacology & Toxicology, 2016
Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the ... more Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal tract and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic-metabolizing enzymes (XMEs) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II conjugating enzymes, and phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 4 weeks; thereafter, the mRNA and protein expression levels of several XMEs and transporters were determined by RT-PCR and Western blot analysis, respectively. Real-time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas it inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal, but not hepatic, CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P-gp, MRP2 and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment.
Potential inhibitory effect of herbal medicines on rat hepatic cytochrome P450 2D gene expression and metabolic activity
Pharmazie
The aim of current study was to investigate the effect of some commonly used medicinal herbs on t... more The aim of current study was to investigate the effect of some commonly used medicinal herbs on the regulation of rat CYP2D gene expression and its metabolic activity. Wistar albino rats were treated for seven consecutive days with selected doses of five commonly used herbs (Trigonella foenum-graecum, Ferula asafoetida, Nigella sativa, Commiphora myrrha and Lepidium sativum). Thereafter, rat livers were harvested and CYP2D mRNA levels were determined by RT-PCR. The metabolic activity of CYP2D was performed on rat hepatic microsomes using dextromethorphan as specific substrate. All investigated herbs produced inhibition of CYP2D mRNA expression and metabolic activity. The inhibitory potential of investigated herbs on rat CYP2D mRNA was in the following order: Commiphora myrrha > Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Ferula asafoetida. Whereas, the inhibitory potential of investigated herbs on CYP2D mediated enzyme metabolic activity was found in ...
This paper proposes a methodology to prepare corpora in Arabic language from online social networ... more This paper proposes a methodology to prepare corpora in Arabic language from online social network (OSN) and review site for Sentiment Analysis (SA) task. The paper also proposes a methodology for generating a stopword list from the prepared corpora. The aim of the paper is to investigate the effect of removing stopwords on the SA task. The problem is that the stopwords lists generated before were on Modern Standard Arabic (MSA) which is not the common language used in OSN. We have generated a stopword list of Egyptian dialect and a corpus-based list to be used with the OSN corpora. We compare the efficiency of text classification when using the generated lists along with previously generated lists of MSA and combining the Egyptian dialect list with the MSA list. The text classification was performed using Na\"ive Bayes and Decision Tree classifiers and two feature selection approaches, unigrams and bigram. The experiments show that the general lists containing the Egyptian dia...
Metformin inhibits 2,7-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway
Toxicology and Applied Pharmacology, 2015
Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antio... more Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism.
Drug Research, 2014
such as cholesterol, corticosteroids and fatty acids. The most important feature of the CYP enzym... more such as cholesterol, corticosteroids and fatty acids. The most important feature of the CYP enzymes is its unique role in the intra-cellular metabolism by incorporation of an oxygen atom stereo-specifi cally into inert chemical bonds [ 3 , 5 ] . Among CYPs, CYP2C subfamily represents an important group of isozymes for drug metabolism in human, as these constitute about 16 % of the total hepatic CYP complement, and is known to be responsible for the metabolism of roughly 15 % of drug oxidations. Human CYP2C9 is a major CYP enzyme involved in the metabolism of a wide range of therapeutic agents, including non-steroidal anti-infl ammatory drugs, oral anticoagulants and oral hypoglycemic agents . CYP2C9 also contributes to the metabolism of fatty acids, prostanoids and steroid hormones. The rat forms of the human CYP2C9 equivalent CYP2C isoforms include CYP2C6 and CYP2C11, with CYP2C11 being a 77 % homologue of the human CYP2C9 and the more abundantly expressed CYP in rat .
Regulation of TNF-α and NF-kB activation through the JAK/STAT signaling pathway downstream of Histamine 4 receptor in a rat model of LPS-induced joint inflammation
Immunobiology, 2015
Molecular Immunology, 2015
Increasing indication is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulat... more Increasing indication is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulation of inflammatory/immune responses. The aim of the present study was to determine the potential antiinflammatory effects of PARP-1 inhibitor 5-aminoisoquinolinone (5-AIQ) to explore the role of PARP-1 inhibitor in a mouse model of carrageenan-induced lung inflammation. A single dose of 5-AIQ (1.5 mg/kg) was administered intraperitoneally (i.p.) 1 h before-carrageenan (Cg) administration. We assessed the effects of 5-AIQ treatment on CD25 + , GITR + , CD25 + GITR + , IL-17 + and Foxp3 + cells which were investigated using flowcytometry in pleural exudates and heparinized blood. We also evaluated mRNA expressions of IL-6, TNF-␣, IL-1, IL-10, CD11a, l-selectin (CD62L), ICAM-1, MCP-1, iNOS and COX-2 in the lung tissue. We further examined the effects of 5-AIQ on the key mediators of inflammation, namely COX-2, STAT-3, NF-kB p65, PARP-1, IkB-␣ and IL-4 protein expression in the lung tissue using western blotting. The results illustrated that the numbers of T cell subsets, IL-17 + cytokine levels were markedly increased and Foxp3 + production decreased in the Cg group. Furthermore, Cg-induced up-regulation of adhesion molecules, pro-inflammatory mediators and chemokine expressions. Western blot analysis revealed an increased protein expressions of COX-2, STAT-3 NF-kB p65 and PARP-1 and decreased IkB-␣ and IL-4 in the Cg group. PARP-1 inhibitor via 5-AIQ treatment reverses the action significantly of all the previously mentioned effects. Moreover, histological examinations revealed anti-inflammatory effects of 5-AIQ, whereas Cggroup aggravated Cg-induced inflammation. Present findings demonstrate the potent anti-inflammatory action of the PARP-1 inhibitor in acute lung injury induced by carrageenan.
Naringin Attenuates the Development of Carrageenan-Induced Acute Lung Inflammation Through Inhibition of NF-κb, STAT3 and Pro-Inflammatory Mediators and Enhancement of IκBα and Anti-Inflammatory Cytokines
Inflammation, 2014
Cardiovascular Toxicology, 2014
mRNA levels, but did alter the a-MHC level. Whereas at the protein level, MAPK inhibitors general... more mRNA levels, but did alter the a-MHC level. Whereas at the protein level, MAPK inhibitors generally decreased the SUN-induced BNP, whereas only SB and U0 increased b-MHC protein levels with no effect on a-MHC, which were associated with a significant decrease in cell size. Together, these results indicate that SUN induced hypertrophic gene expression through MAPK-dependent mechanisms.
Effects of renal diseases on the regulation and expression of renal and hepatic drug-metabolizing enzymes: a review
Xenobiotica, 2004
1. The activity of drug-metabolizing enzymes (DMEs) in extrahepatic organs is highest in the kidn... more 1. The activity of drug-metabolizing enzymes (DMEs) in extrahepatic organs is highest in the kidneys. Generally, the kidneys contain most, if not all, of the DMEs found in the liver. Surprisingly, some of these DMEs show higher activity in the kidneys than in the liver. 2. Most of the renal DMEs are localized in the cortex of the kidneys, especially in the proximal tubules. DMEs are also found in the distal tubules and collecting ducts. 3. Renal diseases such as acute and chronic renal failure and renal cell carcinoma alter the regulation of both hepatic and extrahepatic phase I and II DMEs. Changes in the expression of these DMEs seem to be tissue and species specific. 4. Generally, there is significant down-regulation of most of the phase I and a few of phase II DMEs at the protein, mRNA and activity levels. Unfortunately, the mechanisms leading to the alteration in DMEs in renal diseases remain unclear, although many theories have been made. 5. The presence of some circulating factors such as cytokines, nitric oxide, parathyroid hormones and increased intracellular calcium play a role in the regulation of DMEs in renal diseases.
The role of aryl hydrocarbon receptor signaling pathway in cardiotoxicity of acute lead intoxication in vivo and in vitro rat model
Toxicology, 2013
Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs ... more Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs in the body including the kidneys, liver, and central nervous system. However, Pb(2+)-induced cardiotoxicity has never been investigated yet and the exact mechanism of Pb(2+) associated cardiotoxicity has not been studied. The current study was designed to investigate the potential effect of Pb(2+) to induce cardiotoxicity in vivo and in vitro rat model and to explore the molecular mechanisms and the role of aryl hydrocarbon receptor (AhR) and regulated gene, cytochrome P4501A1 (CYP1A1), in Pb(2+)-mediated cardiotoxicity. For these purposes, Wistar albino rats were treated with Pb(2+) (25, 50 and 100mg/kg, i.p.) for three days and the effects on physiological and histopathological parameters of cardiotoxicity were determined. At the in vitro level, rat cardiomyocyte H9c2 cell lines were incubated with increasing concentration of Pb(2+) (25, 50, and 100 μM) and the expression of hypertrophic genes, α- and β-myosin heavy chain (α-MHC and β-MHC), brain Natriuretic Peptide (BNP), and CYP1A1 were determined at the mRNA and protein levels using real-time PCR and Western blot analysis, respectively. The results showed that Pb(2+) significantly induced cardiotoxicity and heart failure as evidenced by increase cardiac enzymes, lactate dehydrogenase and creatine kinase and changes in histopathology in vivo. In addition, Pb(2+) treatment induced β-MHC and BNP whereas inhibited α-MHC mRNA and protein levels in vivo in a dose-dependent manner. In contrast, at the in vitro level, Pb(2+) treatment induced both β-MHC and α-MHC mRNA levels in time- and dose-dependent manner. Importantly, these changes were accompanied with a proportional increase in the expression of CYP1A1 mRNA and protein expression levels, suggesting a role for the CYP1A1 in cardiotoxicity. The direct evidence for the involvement of CYP1A1 in the induction of cardiotoxicity by Pb(2+) was evidenced by the ability of AhR antagonist, resveratrol, to significantly inhibit the Pb(2+)-modulated effect on β-MHC and α-MHC mRNAs. It was concluded that acute lead exposure induced cardiotoxicity through AhR/CYP1A1-mediated mechanism.
Induction of Cytochrome P450 1A1 by Ketoconazole and Itraconazole but not Fluconazole in Murine and Human Hepatoma Cell Lines
Toxicological Sciences, 2007
Azole antifungal agents are widely prescribed drugs for the treatment of systemic fungal infectio... more Azole antifungal agents are widely prescribed drugs for the treatment of systemic fungal infections; however, since their introduction into the market, increasing evidences of hepatotoxicity have been reported. Therefore, we examined here the ability of three structurally different antifungal drugs, ketoconazole (KTZ), itraconazole (ITZ), and fluconazole (FLZ) to induce the CYP1A1, an enzyme known to play an important role in chemical activation of xenobiotics to toxic metabolites. KTZ and ITZ, but not FLZ, induced the CYP1A1 in murine Hepa 1c1c7 and human HepG2 hepatoma cells at the mRNA, protein and activity levels in a concentration- and time-dependent manner. The increases in Cyp1a1 mRNA levels mediated by KTZ and ITZ were completely blocked by the RNA synthesis inhibitor, actinomycin D, whereas the level of existing mRNA was not altered, implying a requirement of de novo RNA synthesis through a transcriptional mechanism. The ability of these drugs to directly activate the aryl hydrocarbon receptor (AhR) transformation and hence xenobiotic responsive element's binding was strongly correlated with their abilities to induce luciferase activity. Inhibition studies showed that KTZ and ITZ, in addition to being CYP1A1 inducers, are substrates and competitive inhibitors. This study provides the first evidence for the ability of KTZ and ITZ to induce the CYP1A1 gene expression through an AhR-dependent mechanism, and suggests a novel mechanism of the KTZ- and ITZ-mediated toxicities.
Toxicological Sciences, 2005
We recently demonstrated that heavy metals, Hg 2+ , Pb 2+ , and Cu 2+ induced Cyp1a1 gene express... more We recently demonstrated that heavy metals, Hg 2+ , Pb 2+ , and Cu 2+ induced Cyp1a1 gene expression, yet the mechanisms involved remain unknown. To explore the molecular mechanisms involved in the modulation of Cyp1a1 by heavy metals, Hepa 1c1c7 cells were treated with the metals in the presence and absence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Cyp1a1 inducer. Time-dependent effect study showed that all metals significantly induced the basal Cyp1a1 mRNA. This was apparent 3 h after treatment, and levels remained elevated for at least 24 h. At the inducible level, Hg 2+ and Pb 2+ further increased, while Cu 2+ decreased, the TCDD-mediated induction of Cyp1a1 mRNA. The RNA synthesis inhibitor, actinomycin D, completely blocked the Cyp1a1 induction by heavy metals. The protein synthesis inhibitor, cycloheximide, and 26S proteasome inhibitor, carbobenzoxy-L-leucyl-L-leucyl-leucinal (MG-132), superinduced the metal-mediated induction of Cyp1a1 mRNA. In addition, all three metals induced aryl hydrocarbon receptor/xenobioticresponsive element (AhR/XRE) binding, suggesting an AhRdependent mechanism. Cyp1a1 mRNA and protein decay experiments showed that the three metals did not significantly affect the half-life of mRNA; however, they significantly decreased the degradation rate of its protein, implying a posttranslational regulation of the Cyp1a1 by the heavy metals. A significant decrease in TCDD-mediated induction of Cyp1a1 activity associated with an increase in HO-1 mRNA and a decrease in cellular heme content was observed after all metals treatment. This suggests that heme degradation plays a role in reducing Cyp1a1 activity. This is the first demonstration that heavy metals can directly induce Cyp1a1 gene expression in an AhR-dependent manner through transcriptional and posttranslational mechanisms.
Mutagenesis, 2011
The intention of the present study was to answer the question whether the catalytic topoisomerase... more The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposideinduced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.
Molecular and Cellular Biochemistry, 2014
Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine int... more Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose-and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADPribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by upregulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug.
Journal of the Renin-Angiotensin-Aldosterone System, 2014
Introduction: Tacrolimus is frequently used as immunosuppressive agent in organ transplantation b... more Introduction: Tacrolimus is frequently used as immunosuppressive agent in organ transplantation but its clinical use is limited due to its marked nephrotoxicity. Materials and methods: Male Wistar albino rats weighing 150-200 g (10-12 weeks old) were used. Animals were divided into four groups. Group 1 served as control group and received normal saline, group 2 served as toxic group and received 2 mg/kg tacrolimus i.p., group 3 served as treatment group and received 2 mg/kg tacrolimus i.p. followed by 2 mg/kg aliskiren orally and group 4 served as drug per se group and received 2 mg/kg aliskiren orally. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. Results: Treatment with aliskiren decreased the tacrolimus-induced changes in biochemical markers of nephrotoxicity such as blood urea nitrogen and creatinine. Aliskiren also attenuated the effects of tacrolimus on oxidative stress parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that aliskiren attenuated tacrolimus-induced renal damage. Conclusion: These results suggest that aliskiren has protective effects against tacrolimus-induced nephrotoxicity; implying that renin inhibitor may counteract nephrotic syndrome associated with immunosuppressant use.
Drug Metabolism and Disposition, 2005
Running title: Heavy metals and regulation of Nqo1 and Gst ya genes.
Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway
Archives of Toxicology, 2013
Sunitinib (SUN) is a new tyrosine kinase inhibitor that possesses both anti-angiogenic and anti-t... more Sunitinib (SUN) is a new tyrosine kinase inhibitor that possesses both anti-angiogenic and anti-tumor activities. Although SUN has improved survival rate in cancer patients, cardiotoxicity has been reported as a significant side effect. Several studies suggested a role for the aryl hydrocarbon receptor (AhR) and its regulated genes such as cytochrome P4501A1 (CYP1A1) in the pathogenesis of heart failure and cardiac hypertrophy. To test the hypothesis that SUN induces cardiac hypertrophy through the modulation of AhR, Wistar albino rats were treated for 15 and 30 days with increasing doses of SUN (25, 50, and 100 mg/kg), whereas at the in vitro level, rat cardiomyocyte H9c2 cells were incubated with SUN (1, 2.5, and 5 μM). Thereafter, cardiac hypertrophy parameters were determined at the biochemical, histopathology, and gene expression levels. SUN treatment causes increase in cardiac enzymes, changes in histopathology, and induction in several hypertrophic markers. This was associated with proportional increase in the CYP1A1 gene in a concentration- and time-dependent manner. The direct involvement of AhR in the SUN-induced cardiac hypertrophy in H9c2 cells was supported by the ability of resveratrol, an AhR antagonist, to block the SUN-induced hypertrophy and the ability of SB203580, a novel AhR agonist, to potentiate SUN-induced hypertrophic genes. This is the first demonstration that SUN induces hypertrophic genes in vivo and in vitro rat cardiomyocyte through AhR/CYP1A1-mediated mechanism.
Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation
Archives of Toxicology, 2013
Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angioge... more Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7 cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN was completely blocked by the transcriptional inhibitor, actinomycin D; implying that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.
International Journal of Pharmaceutics, 2008
The tissue distribution and hepatic microsomal metabolism of amiodarone were studied in a hyperli... more The tissue distribution and hepatic microsomal metabolism of amiodarone were studied in a hyperlipidemic rat model. Rats were rendered hyperlipidemic by the intraperitoneal injection of poloxamer 407. Other normolipidemic animals given saline in place of poloxamer 407 were used as control animals. After single intravenous injection of amiodarone HCl (25 mg/kg) rats were anesthetized and plasma and tissue specimens were obtained. Liver microsomal protein was harvested and used to measure velocity of desethylamiodarone formation from amiodarone and cytochrome P450 (CYP) protein expression. Hyperlipidemia caused large increases in plasma concentrations of amiodarone. In tissues, however, concentrations of drug selectively increased, decreased or did not change. In heart, the site of action of the drug, as well as liver and spleen, amiodarone concentrations increased. In other tissues such as kidney, lung and brain, concentrations decreased. No changes were seen in fat or thyroid. Decreases were observed in liver metabolic efficiency, and expression of CYP3A1/2 and 2C11. No changes were seen in CYP2B1/2, 2C6, 2D1 or 1A2. This experimental hyperlipidemia caused a complex pattern of changes in tissue distribution of AM. In addition, there are decreases in the expression of some important rat CYP isoenzymes.
Basic & Clinical Pharmacology & Toxicology, 2016
Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the ... more Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal tract and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic-metabolizing enzymes (XMEs) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II conjugating enzymes, and phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 4 weeks; thereafter, the mRNA and protein expression levels of several XMEs and transporters were determined by RT-PCR and Western blot analysis, respectively. Real-time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas it inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal, but not hepatic, CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P-gp, MRP2 and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment.
Potential inhibitory effect of herbal medicines on rat hepatic cytochrome P450 2D gene expression and metabolic activity
Pharmazie
The aim of current study was to investigate the effect of some commonly used medicinal herbs on t... more The aim of current study was to investigate the effect of some commonly used medicinal herbs on the regulation of rat CYP2D gene expression and its metabolic activity. Wistar albino rats were treated for seven consecutive days with selected doses of five commonly used herbs (Trigonella foenum-graecum, Ferula asafoetida, Nigella sativa, Commiphora myrrha and Lepidium sativum). Thereafter, rat livers were harvested and CYP2D mRNA levels were determined by RT-PCR. The metabolic activity of CYP2D was performed on rat hepatic microsomes using dextromethorphan as specific substrate. All investigated herbs produced inhibition of CYP2D mRNA expression and metabolic activity. The inhibitory potential of investigated herbs on rat CYP2D mRNA was in the following order: Commiphora myrrha > Nigella sativa > Lepidium sativum > Trigonella foenum-graecum > Ferula asafoetida. Whereas, the inhibitory potential of investigated herbs on CYP2D mediated enzyme metabolic activity was found in ...
This paper proposes a methodology to prepare corpora in Arabic language from online social networ... more This paper proposes a methodology to prepare corpora in Arabic language from online social network (OSN) and review site for Sentiment Analysis (SA) task. The paper also proposes a methodology for generating a stopword list from the prepared corpora. The aim of the paper is to investigate the effect of removing stopwords on the SA task. The problem is that the stopwords lists generated before were on Modern Standard Arabic (MSA) which is not the common language used in OSN. We have generated a stopword list of Egyptian dialect and a corpus-based list to be used with the OSN corpora. We compare the efficiency of text classification when using the generated lists along with previously generated lists of MSA and combining the Egyptian dialect list with the MSA list. The text classification was performed using Na\"ive Bayes and Decision Tree classifiers and two feature selection approaches, unigrams and bigram. The experiments show that the general lists containing the Egyptian dia...
Metformin inhibits 2,7-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway
Toxicology and Applied Pharmacology, 2015
Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antio... more Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism.
Drug Research, 2014
such as cholesterol, corticosteroids and fatty acids. The most important feature of the CYP enzym... more such as cholesterol, corticosteroids and fatty acids. The most important feature of the CYP enzymes is its unique role in the intra-cellular metabolism by incorporation of an oxygen atom stereo-specifi cally into inert chemical bonds [ 3 , 5 ] . Among CYPs, CYP2C subfamily represents an important group of isozymes for drug metabolism in human, as these constitute about 16 % of the total hepatic CYP complement, and is known to be responsible for the metabolism of roughly 15 % of drug oxidations. Human CYP2C9 is a major CYP enzyme involved in the metabolism of a wide range of therapeutic agents, including non-steroidal anti-infl ammatory drugs, oral anticoagulants and oral hypoglycemic agents . CYP2C9 also contributes to the metabolism of fatty acids, prostanoids and steroid hormones. The rat forms of the human CYP2C9 equivalent CYP2C isoforms include CYP2C6 and CYP2C11, with CYP2C11 being a 77 % homologue of the human CYP2C9 and the more abundantly expressed CYP in rat .
Regulation of TNF-α and NF-kB activation through the JAK/STAT signaling pathway downstream of Histamine 4 receptor in a rat model of LPS-induced joint inflammation
Immunobiology, 2015
Molecular Immunology, 2015
Increasing indication is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulat... more Increasing indication is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulation of inflammatory/immune responses. The aim of the present study was to determine the potential antiinflammatory effects of PARP-1 inhibitor 5-aminoisoquinolinone (5-AIQ) to explore the role of PARP-1 inhibitor in a mouse model of carrageenan-induced lung inflammation. A single dose of 5-AIQ (1.5 mg/kg) was administered intraperitoneally (i.p.) 1 h before-carrageenan (Cg) administration. We assessed the effects of 5-AIQ treatment on CD25 + , GITR + , CD25 + GITR + , IL-17 + and Foxp3 + cells which were investigated using flowcytometry in pleural exudates and heparinized blood. We also evaluated mRNA expressions of IL-6, TNF-␣, IL-1, IL-10, CD11a, l-selectin (CD62L), ICAM-1, MCP-1, iNOS and COX-2 in the lung tissue. We further examined the effects of 5-AIQ on the key mediators of inflammation, namely COX-2, STAT-3, NF-kB p65, PARP-1, IkB-␣ and IL-4 protein expression in the lung tissue using western blotting. The results illustrated that the numbers of T cell subsets, IL-17 + cytokine levels were markedly increased and Foxp3 + production decreased in the Cg group. Furthermore, Cg-induced up-regulation of adhesion molecules, pro-inflammatory mediators and chemokine expressions. Western blot analysis revealed an increased protein expressions of COX-2, STAT-3 NF-kB p65 and PARP-1 and decreased IkB-␣ and IL-4 in the Cg group. PARP-1 inhibitor via 5-AIQ treatment reverses the action significantly of all the previously mentioned effects. Moreover, histological examinations revealed anti-inflammatory effects of 5-AIQ, whereas Cggroup aggravated Cg-induced inflammation. Present findings demonstrate the potent anti-inflammatory action of the PARP-1 inhibitor in acute lung injury induced by carrageenan.
Naringin Attenuates the Development of Carrageenan-Induced Acute Lung Inflammation Through Inhibition of NF-κb, STAT3 and Pro-Inflammatory Mediators and Enhancement of IκBα and Anti-Inflammatory Cytokines
Inflammation, 2014
Cardiovascular Toxicology, 2014
mRNA levels, but did alter the a-MHC level. Whereas at the protein level, MAPK inhibitors general... more mRNA levels, but did alter the a-MHC level. Whereas at the protein level, MAPK inhibitors generally decreased the SUN-induced BNP, whereas only SB and U0 increased b-MHC protein levels with no effect on a-MHC, which were associated with a significant decrease in cell size. Together, these results indicate that SUN induced hypertrophic gene expression through MAPK-dependent mechanisms.
Effects of renal diseases on the regulation and expression of renal and hepatic drug-metabolizing enzymes: a review
Xenobiotica, 2004
1. The activity of drug-metabolizing enzymes (DMEs) in extrahepatic organs is highest in the kidn... more 1. The activity of drug-metabolizing enzymes (DMEs) in extrahepatic organs is highest in the kidneys. Generally, the kidneys contain most, if not all, of the DMEs found in the liver. Surprisingly, some of these DMEs show higher activity in the kidneys than in the liver. 2. Most of the renal DMEs are localized in the cortex of the kidneys, especially in the proximal tubules. DMEs are also found in the distal tubules and collecting ducts. 3. Renal diseases such as acute and chronic renal failure and renal cell carcinoma alter the regulation of both hepatic and extrahepatic phase I and II DMEs. Changes in the expression of these DMEs seem to be tissue and species specific. 4. Generally, there is significant down-regulation of most of the phase I and a few of phase II DMEs at the protein, mRNA and activity levels. Unfortunately, the mechanisms leading to the alteration in DMEs in renal diseases remain unclear, although many theories have been made. 5. The presence of some circulating factors such as cytokines, nitric oxide, parathyroid hormones and increased intracellular calcium play a role in the regulation of DMEs in renal diseases.
The role of aryl hydrocarbon receptor signaling pathway in cardiotoxicity of acute lead intoxication in vivo and in vitro rat model
Toxicology, 2013
Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs ... more Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs in the body including the kidneys, liver, and central nervous system. However, Pb(2+)-induced cardiotoxicity has never been investigated yet and the exact mechanism of Pb(2+) associated cardiotoxicity has not been studied. The current study was designed to investigate the potential effect of Pb(2+) to induce cardiotoxicity in vivo and in vitro rat model and to explore the molecular mechanisms and the role of aryl hydrocarbon receptor (AhR) and regulated gene, cytochrome P4501A1 (CYP1A1), in Pb(2+)-mediated cardiotoxicity. For these purposes, Wistar albino rats were treated with Pb(2+) (25, 50 and 100mg/kg, i.p.) for three days and the effects on physiological and histopathological parameters of cardiotoxicity were determined. At the in vitro level, rat cardiomyocyte H9c2 cell lines were incubated with increasing concentration of Pb(2+) (25, 50, and 100 μM) and the expression of hypertrophic genes, α- and β-myosin heavy chain (α-MHC and β-MHC), brain Natriuretic Peptide (BNP), and CYP1A1 were determined at the mRNA and protein levels using real-time PCR and Western blot analysis, respectively. The results showed that Pb(2+) significantly induced cardiotoxicity and heart failure as evidenced by increase cardiac enzymes, lactate dehydrogenase and creatine kinase and changes in histopathology in vivo. In addition, Pb(2+) treatment induced β-MHC and BNP whereas inhibited α-MHC mRNA and protein levels in vivo in a dose-dependent manner. In contrast, at the in vitro level, Pb(2+) treatment induced both β-MHC and α-MHC mRNA levels in time- and dose-dependent manner. Importantly, these changes were accompanied with a proportional increase in the expression of CYP1A1 mRNA and protein expression levels, suggesting a role for the CYP1A1 in cardiotoxicity. The direct evidence for the involvement of CYP1A1 in the induction of cardiotoxicity by Pb(2+) was evidenced by the ability of AhR antagonist, resveratrol, to significantly inhibit the Pb(2+)-modulated effect on β-MHC and α-MHC mRNAs. It was concluded that acute lead exposure induced cardiotoxicity through AhR/CYP1A1-mediated mechanism.
Induction of Cytochrome P450 1A1 by Ketoconazole and Itraconazole but not Fluconazole in Murine and Human Hepatoma Cell Lines
Toxicological Sciences, 2007
Azole antifungal agents are widely prescribed drugs for the treatment of systemic fungal infectio... more Azole antifungal agents are widely prescribed drugs for the treatment of systemic fungal infections; however, since their introduction into the market, increasing evidences of hepatotoxicity have been reported. Therefore, we examined here the ability of three structurally different antifungal drugs, ketoconazole (KTZ), itraconazole (ITZ), and fluconazole (FLZ) to induce the CYP1A1, an enzyme known to play an important role in chemical activation of xenobiotics to toxic metabolites. KTZ and ITZ, but not FLZ, induced the CYP1A1 in murine Hepa 1c1c7 and human HepG2 hepatoma cells at the mRNA, protein and activity levels in a concentration- and time-dependent manner. The increases in Cyp1a1 mRNA levels mediated by KTZ and ITZ were completely blocked by the RNA synthesis inhibitor, actinomycin D, whereas the level of existing mRNA was not altered, implying a requirement of de novo RNA synthesis through a transcriptional mechanism. The ability of these drugs to directly activate the aryl hydrocarbon receptor (AhR) transformation and hence xenobiotic responsive element's binding was strongly correlated with their abilities to induce luciferase activity. Inhibition studies showed that KTZ and ITZ, in addition to being CYP1A1 inducers, are substrates and competitive inhibitors. This study provides the first evidence for the ability of KTZ and ITZ to induce the CYP1A1 gene expression through an AhR-dependent mechanism, and suggests a novel mechanism of the KTZ- and ITZ-mediated toxicities.
Toxicological Sciences, 2005
We recently demonstrated that heavy metals, Hg 2+ , Pb 2+ , and Cu 2+ induced Cyp1a1 gene express... more We recently demonstrated that heavy metals, Hg 2+ , Pb 2+ , and Cu 2+ induced Cyp1a1 gene expression, yet the mechanisms involved remain unknown. To explore the molecular mechanisms involved in the modulation of Cyp1a1 by heavy metals, Hepa 1c1c7 cells were treated with the metals in the presence and absence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Cyp1a1 inducer. Time-dependent effect study showed that all metals significantly induced the basal Cyp1a1 mRNA. This was apparent 3 h after treatment, and levels remained elevated for at least 24 h. At the inducible level, Hg 2+ and Pb 2+ further increased, while Cu 2+ decreased, the TCDD-mediated induction of Cyp1a1 mRNA. The RNA synthesis inhibitor, actinomycin D, completely blocked the Cyp1a1 induction by heavy metals. The protein synthesis inhibitor, cycloheximide, and 26S proteasome inhibitor, carbobenzoxy-L-leucyl-L-leucyl-leucinal (MG-132), superinduced the metal-mediated induction of Cyp1a1 mRNA. In addition, all three metals induced aryl hydrocarbon receptor/xenobioticresponsive element (AhR/XRE) binding, suggesting an AhRdependent mechanism. Cyp1a1 mRNA and protein decay experiments showed that the three metals did not significantly affect the half-life of mRNA; however, they significantly decreased the degradation rate of its protein, implying a posttranslational regulation of the Cyp1a1 by the heavy metals. A significant decrease in TCDD-mediated induction of Cyp1a1 activity associated with an increase in HO-1 mRNA and a decrease in cellular heme content was observed after all metals treatment. This suggests that heme degradation plays a role in reducing Cyp1a1 activity. This is the first demonstration that heavy metals can directly induce Cyp1a1 gene expression in an AhR-dependent manner through transcriptional and posttranslational mechanisms.
Mutagenesis, 2011
The intention of the present study was to answer the question whether the catalytic topoisomerase... more The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposideinduced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.
Molecular and Cellular Biochemistry, 2014
Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine int... more Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose-and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADPribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by upregulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug.
Journal of the Renin-Angiotensin-Aldosterone System, 2014
Introduction: Tacrolimus is frequently used as immunosuppressive agent in organ transplantation b... more Introduction: Tacrolimus is frequently used as immunosuppressive agent in organ transplantation but its clinical use is limited due to its marked nephrotoxicity. Materials and methods: Male Wistar albino rats weighing 150-200 g (10-12 weeks old) were used. Animals were divided into four groups. Group 1 served as control group and received normal saline, group 2 served as toxic group and received 2 mg/kg tacrolimus i.p., group 3 served as treatment group and received 2 mg/kg tacrolimus i.p. followed by 2 mg/kg aliskiren orally and group 4 served as drug per se group and received 2 mg/kg aliskiren orally. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. Results: Treatment with aliskiren decreased the tacrolimus-induced changes in biochemical markers of nephrotoxicity such as blood urea nitrogen and creatinine. Aliskiren also attenuated the effects of tacrolimus on oxidative stress parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that aliskiren attenuated tacrolimus-induced renal damage. Conclusion: These results suggest that aliskiren has protective effects against tacrolimus-induced nephrotoxicity; implying that renin inhibitor may counteract nephrotic syndrome associated with immunosuppressant use.
Drug Metabolism and Disposition, 2005
Running title: Heavy metals and regulation of Nqo1 and Gst ya genes.
Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway
Archives of Toxicology, 2013
Sunitinib (SUN) is a new tyrosine kinase inhibitor that possesses both anti-angiogenic and anti-t... more Sunitinib (SUN) is a new tyrosine kinase inhibitor that possesses both anti-angiogenic and anti-tumor activities. Although SUN has improved survival rate in cancer patients, cardiotoxicity has been reported as a significant side effect. Several studies suggested a role for the aryl hydrocarbon receptor (AhR) and its regulated genes such as cytochrome P4501A1 (CYP1A1) in the pathogenesis of heart failure and cardiac hypertrophy. To test the hypothesis that SUN induces cardiac hypertrophy through the modulation of AhR, Wistar albino rats were treated for 15 and 30 days with increasing doses of SUN (25, 50, and 100 mg/kg), whereas at the in vitro level, rat cardiomyocyte H9c2 cells were incubated with SUN (1, 2.5, and 5 μM). Thereafter, cardiac hypertrophy parameters were determined at the biochemical, histopathology, and gene expression levels. SUN treatment causes increase in cardiac enzymes, changes in histopathology, and induction in several hypertrophic markers. This was associated with proportional increase in the CYP1A1 gene in a concentration- and time-dependent manner. The direct involvement of AhR in the SUN-induced cardiac hypertrophy in H9c2 cells was supported by the ability of resveratrol, an AhR antagonist, to block the SUN-induced hypertrophy and the ability of SB203580, a novel AhR agonist, to potentiate SUN-induced hypertrophic genes. This is the first demonstration that SUN induces hypertrophic genes in vivo and in vitro rat cardiomyocyte through AhR/CYP1A1-mediated mechanism.
Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation
Archives of Toxicology, 2013
Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angioge... more Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7 cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN was completely blocked by the transcriptional inhibitor, actinomycin D; implying that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.
International Journal of Pharmaceutics, 2008
The tissue distribution and hepatic microsomal metabolism of amiodarone were studied in a hyperli... more The tissue distribution and hepatic microsomal metabolism of amiodarone were studied in a hyperlipidemic rat model. Rats were rendered hyperlipidemic by the intraperitoneal injection of poloxamer 407. Other normolipidemic animals given saline in place of poloxamer 407 were used as control animals. After single intravenous injection of amiodarone HCl (25 mg/kg) rats were anesthetized and plasma and tissue specimens were obtained. Liver microsomal protein was harvested and used to measure velocity of desethylamiodarone formation from amiodarone and cytochrome P450 (CYP) protein expression. Hyperlipidemia caused large increases in plasma concentrations of amiodarone. In tissues, however, concentrations of drug selectively increased, decreased or did not change. In heart, the site of action of the drug, as well as liver and spleen, amiodarone concentrations increased. In other tissues such as kidney, lung and brain, concentrations decreased. No changes were seen in fat or thyroid. Decreases were observed in liver metabolic efficiency, and expression of CYP3A1/2 and 2C11. No changes were seen in CYP2B1/2, 2C6, 2D1 or 1A2. This experimental hyperlipidemia caused a complex pattern of changes in tissue distribution of AM. In addition, there are decreases in the expression of some important rat CYP isoenzymes.