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Dive into the research topics where Ayman O. S. El-Kadi is active.

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Featured researches published by Ayman O. S. El-Kadi.


Current Drug Metabolism | 2007

Chemoprotective and carcinogenic effects of tert-butylhydroquinone and its metabolites.

Negar Gharavi; Susan Haggarty; Ayman O. S. El-Kadi

Tert-butylhydroquinone (tBHQ) has been commonly used as a synthetic food antioxidant to prevent oils and fats from oxidative deterioration and rancidity due to its potent anti-lipid peroxidation activity. In North America, the maximum level of tBHQ allowed in fat products is 0.02% with an acceptable daily intake of 0-0.7 mg/kg body weight. Extensive studies have demonstrated that tBHQ exhibit anti-carcinogenic effect. The ability of tBHQ to induce phase II xenobiotic metabolizing enzymes through an Nrf2-dependent pathway is thought to be responsible for the observed protective effect of tBHQ. It has been proposed that tBHQ enhances Nrf2-mediated transcription by promoting reactive oxygen species-mediated dissociation of Nrf2-Keap1, Nrf2 stabilization, phosphatidylinositol 3-kinase (PI3K)/Akt activity, and MAPK pathway activation. In contrast to the beneficial effects of tBHQ, a number of studies have shown that chronic exposure to tBHQ may induce carcinogenicity. However, the precise mechanisms of tBHQ carcinogenicity are not well understood. The toxicity or carcinogenicity of tBHQ has been attributed to the formation of reactive GSH-conjugates, generation of reactive species, CYP1A1 induction, caspase activation and reduced GSH/ATP levels. This review provides an account of recent mechanisms proposed for both chemoprotective and carcinogenic effect of tBHQ.


Current Drug Metabolism | 2004

The Effect of Liver Cirrhosis on the Regulation and Expression of Drug Metabolizing Enzymes

Reem H. Elbekai; Hesham M. Korashy; Ayman O. S. El-Kadi

Cirrhosis is the end stage of many forms of liver pathologies including hepatitis. The liver is known for its vital role in the processing of xenobiotics, including drugs and toxic compounds. Cirrhosis causes changes in the architecture of the liver leading to changes in blood flow, protein binding, and drug metabolizing enzymes. Drug metabolizing enzymes are primarily decreased due to loss of liver tissue. However, not all enzyme activities are reduced and some are only altered in specific cases. There is a great deal of discrepancy between various reports on cytochrome p450 alterations in liver cirrhosis, likely due to differences in disease severity and other underlying conditions. In general, however, CYP1A and CYP3A levels and related enzyme activities are usually reduced and CYP2C, CYP2A, and CYP2B are mostly unaltered. Both alcohol dehyrogenases and aldehyde dehydrogenases are altered in liver cirrhosis, although the etiology of the disease may determine the expression of alcohol dehydrogenases. Glucuronidation is mainly preserved, but there are a number of factors that determine whether glucuronidation is affected in patients with liver cirrhosis. Low sulphation rates are usually found in patients with liver disease but a decrease in sulfatase activity compensates for the decrease in sulphation rates. In all cases, a reduction in drug metabolizing enzyme activities in liver cirrhosis contributes to decreased clearance of drugs seen in patients with liver abnormalities. The reduction in drug metabolizing enzyme activity must be taken into consideration when adjusting doses, especially in patients with severe liver disease.


Journal of Pharmacy and Pharmaceutical Sciences | 2008

The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

Marwa E. Elsherbiny; Ayman O. S. El-Kadi; Dion R. Brocks

PURPOSE To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.


Drug Metabolism and Disposition | 2005

TRANSCRIPTIONAL REGULATION OF THE NAD(P)H:QUINONE OXIDOREDUCTASE 1 AND GLUTATHIONE S-TRANSFERASE YA GENES BY MERCURY, LEAD, AND COPPER

Hesham M. Korashy; Ayman O. S. El-Kadi

Recently, we demonstrated the ability of heavy metals, particularly Hg2+, Pb2+, and Cu2+, to differentially modulate in Hepa 1c1c7 cells the expression of the phase II xenobiotic metabolizing enzymes NAD(P)H:quinone oxidoreductase 1 (Nqo1) and glutathione S-transferase subunit Ya (Gst ya) genes, yet the mechanisms involved remain unknown. To investigate the molecular mechanisms involved in the regulation of Nqo1 and Gst ya genes by heavy metals, Hepa 1c1c7 cells were treated with Hg2+, Pb2+, or Cu2+ in the presence and absence of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent inducer of Nqo1, Gst ya, and Cyp1a1 genes. Analysis of the time-dependent effect of heavy metals revealed that Hg2+ and Pb2+ increased whereas Cu2+ inhibited the constitutive and inducible expression of Nqo1 and Gst ya mRNAs in a time-dependent manner. The RNA synthesis inhibitor actinomycin D significantly inhibited the Nqo1 and Gst ya mRNA induction in response to metals, indicating a requirement of de novo RNA synthesis. The protein synthesis inhibitor cycloheximide significantly inhibited metal-mediated induction of Nqo1 and Gst ya mRNAs, which coincided with a decrease in the nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression, implying the requirement of Nrf2 protein synthesis for the induction of these genes. Furthermore, inhibition of Nrf2 protein degradation by carbobenzoxy-l-leucyl-l-leucyl-leucinal (MG-132), a 26S proteasome inhibitor, significantly reversed the cycloheximide-mediated inhibition of Nqo1 and Gst ya mRNAs, which coincided with an increase in the expression of Nrf2, confirming that a transcriptional mechanism is involved. Nqo1 and Gst ya mRNA and protein decay experiments revealed lack of post-transcriptional and post-translational mechanisms. This is the first demonstration that heavy metals regulate the expression of Nqo1 and Gst ya genes through a transcriptional mechanism.


Life Sciences | 2001

L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction.

Maxime M. Barakat; Ayman O. S. El-Kadi; Patrick du Souich

A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.


Drug Metabolism and Disposition | 2005

Determination of the enzyme(s) involved in the metabolism of amiodarone in liver and intestine of rat: the contribution of cytochrome P450 3A isoforms.

Anooshirvan Shayeganpour; Ayman O. S. El-Kadi; Dion R. Brocks

In humans, cytochrome P450 3A (CYP3A4) is a major enzyme involved in the metabolism of amiodarone (AM) to its major metabolite, desethylamiodarone (DEA). In rat, a commonly used animal model, metabolism of AM has not been well studied. To determine whether DEA is formed by CYP3A isoenzymes in the rat, microsomal protein was harvested from liver and intestine of male Sprague-Dawley rats. The metabolism of AM in each tissue was assessed utilizing chemical and immunological inhibitors. Ketoconazole, a presumed inhibitor of CYP3A1/2, significantly inhibited formation of DEA by hepatic and intestinal microsomes. However, based on the DEA formation kinetics in both microsomal preparations, it appeared that more than one cytochrome P450 enzyme was involved in the process. Coincubation of AM with microsomes and anti-CYP3A2 confirmed the role of CYP3A2 in the metabolism of AM in liver. DEA was also formed by rat recombinant CYP1A1 and CYP3A1, and was inhibited by ketoconazole; hence the participation of these enzymes in the intestinal DEA formation is likely. However, anti-CYP2B1/2 or -CYP1A2 antibodies had no effect on DEA formation. In rats given oral or intravenous AM, oral ketoconazole caused significant increases in area under the concentration versus time curve (AUC) of oral and i.v. treated rats and greater than 50% decreases in the total body clearance and Vdss of i.v. treated rats. Although low to undetectable concentrations of DEA were a limitation for determination of AUC of DEA in vivo, it was confirmed that ketoconazole could cause a significant increase in AM concentrations in rat.


British Journal of Pharmacology | 1997

Down‐regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver

Ayman O. S. El-Kadi; Hélène Maurice; Huy Ong; Patrick du Souich

Infection and inflammation trigger a cascade of mediators that eventually will down‐regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute inflammatory reaction (AIR) induced by the s.c. injection of turpentine (5ml), and in the serum of humans with an acute upper respiratory tract viral infection. Hepatocytes from control (HCONT) rabbits and rabbits with an AIR (HINFLA) were isolated and cultured. Compared with HCONT in HINFLA the production of theophylline metabolites, 3‐methylxanthine (3MX), 1‐methyluric acid (1MU), and 1,3‐dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of HINFLA with serum of rabbits with an AIR (RSINFLA) for 4h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RSINFLA obtained 6, 12 and 24h after the injection of turpentine showed the same ability to down‐regulate hepatic P450 as the serum obtained at 48h. The efficacy (Emax) of RSINFLA to inhibit the formation of theophylline metabolites differed, i.e. 1,3DMU>1MU>3MX, and the potency of serum mediators (IC50) was similar for 3MX and 1MU, but lower for 1,3DMU. Incubation of serum of human volunteers (HSINFLA) with a viral infection with HCONT or HINFLA reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HSINFLA depressed 1,3DMU more efficiently than 3MX and 1MU. HSINFLA reduced 3MX with greater efficacy than did RSINFLA. Potency was very variable but not different from rabbits. It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HSINFLA or RSINFLA is closely associated with the increase in lipid peroxidation (r2=0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 down‐regulation.


British Journal of Pharmacology | 1999

Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits

J Kurdi; Hélène Maurice; Ayman O. S. El-Kadi; Huy Ong; S. Dalkara; P M Bélanger; P. du Souich

To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3‐methylcholanthrene (3MC) pre‐treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73±0.43 to 1.48±0.13 ml min−1 kg−1 (P<0.05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3‐methylxanthine (3MX), 1‐methyluric acid (1MU) and 1,3‐dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. Turpentine‐induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. Pre‐treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre‐treatment with 3MC prevented the hypoxia‐induced decrease in amount and activity of the P450. It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre‐treatment with 3MC prevents the hypoxia‐induced depression of the P450.


Drug Metabolism and Disposition | 2008

Down-Regulation of the Carcinogen-Metabolizing Enzyme Cytochrome P450 1a1 by Vanadium

Anwar Anwar-Mohamed; Ayman O. S. El-Kadi

Vanadium (V5+), a heavy metal contaminant with important toxicological consequences, has received considerable attention as an anticancer agent, although the mechanisms remain unknown. As a first step to investigate these mechanisms, we examined the effect of V5+ (as ammonium metavanadate, NH4VO3) on the expression of the aryl hydrocarbon receptor (AhR)-regulated gene: cytochrome P450 1a1 (Cyp1a1) at each step of the AhR signal transduction pathway, using Hepa 1c1c7 cells. Our results showed a significant reduction in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of Cyp1a1 mRNA, protein and activity levels after V5+ treatments in a dose-dependent manner. Investigation of the effect of coexposure to V5+ and TCDD at transcriptional levels revealed that V5+ significantly inhibited TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. Furthermore, despite not affecting the direct activation of the cytosolic AhR by TCDD and subsequently transforming it to a DNA-binding form, V5+ inhibited the nuclear accumulation of liganded AhR and subsequent formation of the AhR/aryl hydrocarbon nuclear translocator (Arnt)/xenobiotic responsive element (XRE) complex. Importantly, the V5+-mediated inhibition of AhR/Arnt/XRE complex formation coincided with a significant decrease in ecto-ATPase activity. Looking at the post-transcriptional and post-translational effects of V5+ on existing Cyp1a1 mRNA and protein levels, we showed that V5+ did not affect Cyp1a1 mRNA or protein stability, thus eliminating possible role of V5+ in modifying Cyp1a1 gene expression through these mechanisms. This study provides the first evidence that V5+ down-regulates the expression of Cyp1a1 at the transcriptional level through an ATP-dependent mechanism.


Current Drug Metabolism | 2013

20-Hydroxyeicosatetraenoic Acid is a Potential Therapeutic Target in Cardiovascular Diseases

Osama H. Elshenawy; Anwar Anwar-Mohamed; Ayman O. S. El-Kadi

Arachidonic acid (AA) is metabolized by enzymes of the cytochrome P450 (CYP) 4A and CYP4F subfamilies to 20- hydroxyeicosatetraeonic acid (20-HETE), which plays an important role in the cardiovascular system. In the current work, we reviewed the formation of 20-HETE in different species by different CYPs; 20-HETE metabolism by cyclooxygenases (COXs) and different isomerases; and the current available inducers and inhibitors of 20-HETE formation in addition to its agonists and antagonists. Moreover we reviewed the negative role of 20-HETE in cardiac hypertrophy, cardiotoxicity, diabetic cardiomyopathy, and in ischemia/reperfusion (I/R) injury. Lastly, we reviewed the role of 20-HETE in different hypertension models such as the renin/angiotensin II model, Goldblatt model, spontaneously hypertensive rat model, androgen-induced model, slat- and deoxycorticosterone acetate (DOCA)-salt-induced models, and high fat diet model. 20-HETE can affect pro- and anti-hypertensive mechanisms dependent upon where, when, and by which isoform it has been produced. In contrast to hypertension we also reviewed the role of 20-HETE in endotoxin-induced hypotension and the natriuretic effects of 20-HETE. Based on the recent studies, 20-HETE production and/or action might be a therapeutic target to protect against the initiation and progression of cardiovascular diseases.

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