ابقى على تواصل

بريد إلكتروني info.ph@uoz.edu.ly
هاتف 00218910000000

أعضاء هيئة التدريس

الرئيسية // أعضاء هيئة التدريس // عيسى امحمد العمياني عمارة

عيسى امحمد العمياني عمارة

عميد كلية الطب البشري


عضو هيئة تدريس قار

المؤهل العلمي: دكتوراه

الدرجة العلمية: أستاذ مساعد

التخصص: Molecular Pharmacology - Pharmacologist

قسم علم الأدوية - كلية الطب البشري - الزنتان

حول عيسى

‎د.عيسى امحمد العمياني عمارة ‎- استاذ مساعد في تخصص علم الادوية الجزئية ‎- تخرج من كلية الصيدلة بجامعة طرابلس ‎- تحصل على درجة الماجستير في الصيدلة السريرية من جامعة العلوم الماليزية ‎- عمل لمدة اربعة سنوات كمحاضر مساعد في جامعة الجبل الغربي. حيث نصب عميدا لكلية طب الاسنان الزنتان . ‎- تحصل على درجة الدكتوراة في تخصص علم الادوية الجزئية بمرتبة الشرف من جامعة البرتا بكندا . ‎- عمل لمدة عامين في معهد امراض السرطان بجامعة البرتا بكندا. ‎- عمل لمدة سنة في قسم طب الاطفال بالمستشفى الجامعي بجامعة البرتا ، كندا. ‎- خلال تواجده بجامعة البرتا قام بتدريس طلاب كليتي الطب والصيدلة واعطى العديد من الكورسات المتعلقة بتخصصه. ‎- عمل بدرجة استاذ مساعد لمدة عامين في جامعة جازان بالمملكة العربية السعودية. ‎- له العديد من الابحاث العلمية المنشورة في مجلات عالمية وذات مستوى عالي. ‎- كلف وكيل لوزارة الصحة بحكومة الوفاق الوطني . ‎- أستقال من منصبه كوكيل وزارة ورجع لسابق عمله بالجامعة ويشغل الان عميدا لكلية الطب البشري بجامعة الزنتان .

المنشورات العلمية
Modulation of TCDD induced Cyp1a1 mRNA by the Co-repressor SMRT
Journal Article

Environmental factors are known to influence carcinogenesis. Procarcinogens, such as heterocyclic amines (HAs) and polycyclic aromatic hydrocarbons (PAHs), are examples of these environmental factors. Procarcinogens are chemically inert and require bioactivation, via enzymes such as Cytochrome P450 (CYP). CYP1A1 isoform, regulated by Aryl hydrocarbon receptor (AhR), plays a significant role in the bioactivation of PAHs and HAs. AhR has multiple co-activators and co-repressors, of which SMRT (silencing mediator for retinoid and thyroid hormone receptors) has been identified as a major co-repressor for AhR. In the present study we examined the effect of SMRT over expression on the Cyp1a1 mRNA levels in murine hepatoma Hepa 1c1c7 cell line. Hepa 1c1c7 cells were maintained in Dulbecco's modified Eagle's medium (DMEM), and competent cells were successfully produced using calcium chloride method. Cells were transformed using plasmid DNA and Lipofectamine. TCDD was employed as an inducing agent for CYP1A1. Total cellular RNA was isolated and real-time PCR of Cyp1a1 was conducted. Statistical analysis was conducted using one-way analysis of variance (ANOVA) followed by Student–Newman–Keul’s test. Our results showed that, cells transfected with the co-repressor SMRT has lower TCDD-mediated induction of Cyp1a1 mRNA without affecting constitutive Cyp1a1 mRNA levels, i.e., SMRT was able to significantly decrease inducible Cyp1a1 mRNA levels in Hepa 1c1c7 cells. Moreover, our work demonstrated that calcium chloride is a convenient method for routine transformation. Our work will open new avenues for treatment of carcinogenesis involving CYP1A1 inducing carcinogens.

 


Issa Emhemmed Alemyani Amara, (03-2023), Mediterrianian Journal of Pharmacy and Pharmaceutical Sciences: Elsevier, 3

Prevalence of Anxiety and Depression Among Medical Students in Libya During the Covid-19 Pandemic: A Cross Sectional Study.
Journal Article

Background: Medical students have been shown through multiple studies to be more susceptible to stress and depression than the rest of the population. Libyan students specifically have to undergo the challenges of becoming a doctor while living in the terrifying and stressful outcomes of the Libyan civil war. And the spread of COVID-19 has added to these stressors.

Objective: This study aimed to determine prevalence of depression and anxiety among Libyan medical students and analyze the causing factors.

Methods: A cross sectional study was conducted using an online survey. The survey used the K-10 Kessler psychological distress scale which is a self administered questionnaire used to measure the level of distress. 

Results: A total of 1348 students from 16 Libyan medical schools across the 5 years of study completed the survey. 992 (73.6%) were female students and 356 (26.4%) were male. The mean age (SD) was 22.09 (2.56).

Out of the 1348 participants, 638 (47.3%) scored for severe mental disorder. 213 (15.8%) scored for moderate mental disorder and 200 (14.8%) presented with mild mental disorder. 297 (22%) of the students are likely to be well according to the K-10 psychological distress scale. Out of the students who have had their houses displaced due to the war, 66.3% have presented with moderate to severe mental disorder.

 235 students (17.4%) have reported having suicidal thoughts throughout their time in medical school.

Conclusion: In comparison to similar studies done in other countries, Libyan students scored a higher prevalence of depression. The stress of the current political state of the country and the COVID-19 pandemic were shown to be contributing factors.


Issa Emhemmed Alemyani Amara, (12-2022), Al Jabal Scientific Journal: University of Zintan, 5

Neuroprotective Effect of Coffee and Tea on Haloperidol-Induced Parkinson's Disease in Rat Model
Journal Article

Background:Coffee and Tea are very popular beverages in Libyan society. They contain many bioactive substances such as polyphenols and catchiness that could have some effects for instance; antioxidant activity. The way of preparation of tea and coffee drinks are different among society. For example, in Libya tea drink is prepared by boiling the crude of fresh tea for 10 min. Therefore, the method of extraction could influence the type and quality of extracted substances. Aims: The goal of the current study was to examine the neuroprotective properties of coffee and tea beverages made by using traditional Libyan techniqueson Parkinson's disease like symptoms induced by haloperidol.Methods: Different tea and coffee beverages (treatment) were prepared and given to rats in a concentration 10%w/v for 3 consecutive weeks.Tea and coffee beverages were made as Libyans do. At day 21, rats were injected IP with 1mg/kg of haloperidol, afterward, the behavioral and motor parameters for Parkinson’s disease were tested.Results:Coffee and Tea treated groups showed significant improvement (p > 0.05)inthe behavioral activity, and in muscle coordination. Also there was a decrease in oxidation markers as treatment resulted in an elevation of glutathione reductase and decreasing in Malondialdehyde levels. In addition, the histopathological investigation showed a reduction in haloperidol induced damage in substantia nigra.Conclusion:The results showeda possible neuroprotective effect of Coffee and Tea against PD.The mechanism of protection might be due to an antioxidant activity.

Issa Emhemmed Alemyani Amara, (03-2022), Libyan Journal of Medical Research: Elsevier, 16

Acute mercury toxicity modulates cytochrome P450, soluble epoxide hydrolase and their associated arachidonic acid metabolites in C57Bl/6 mouse heart
Journal Article

Mercury exposure is associated with increased risk of cardiovascular disease and profound cardiotoxicity. However, the correlation between Hg(2+)-mediated toxicity and alteration in cardiac cytochrome P450s (Cyp) and their dependent arachidonic acid metabolites has never been investigated. Therefore, we investigated the effect of acute mercury toxicity on the expression of Cyp-epoxygenases and Cyp-ω-hydroxylases and their associated arachidonic acid metabolites in mice hearts. In addition, we examined the expression and activity of soluble epoxide hydrolase (sEH) as a key player in arachidonic acid metabolism pathway. Mercury toxicity was induced by a single intraperitoneal injection (IP) of 2.5 mg/kg of mercuric chloride (HgCl₂). Our results showed that mercury treatment caused a significant induction of the cardiac hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); in addition to Cyp1a1, Cyp1b1, Cyp2b9, Cyp2b10, Cyp2b19, Cyp2c29, Cyp2c38, Cyp4a10, Cyp4a12, Cyp4a14, Cyp4f13, Cyp4f15, Cyp4f16 and Cyp4f18 gene expression. Moreover, Hg(2+) significantly increased sEH protein expression and activity levels in hearts of mercury-treated mice, with a consequent decrease in 14,15-, and 11,12-epoxyeicosatrienoic acids (EETs) levels. Whereas the formation of 14,15-, 11,12-, 8,9-dihydroxyeicosatrienoic acids (DHETs) was significantly increased. In conclusion, acute Hg(2+) toxicity modulates the expression of several Cyp and sEH enzymes with a consequent decrease in the cardioprotective EETs which could represent a novel mechanism by which mercury causes progressive cardiotoxicity. Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent Hg(2+)-induced hypertrophy.

Issa Emhemmed Alemyani Amara, (04-2014), Toxicology Letters: Elsevier, 219

.Modulation of cytochrome P450 1 (Cyp1) by vanadium in hepatic tissue and isolated hepatocyte of C57BL/6 mice
Journal Article

The objective of the current study was to investigate the effect of vanadium (V(5+)) on Cyp1 expression and activity in C57BL/6 mice liver and isolated hepatocytes. For this purpose, C57BL6 mice were injected intraperitoneally with V(5+) (5 mg/kg) in the absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (15 μg/kg) for 6 and 24 h. Furthermore, isolated hepatocytes from C57BL6 mice were treated with V(5+) (5, 10, and 20 μM) in the absence and presence of TCDD (1 nM) for 3, 6, 12, and 24 h. In vivo, V(5+) alone did not significantly alter Cyp1a1, Cyp1a2, or Cyp1b1 mRNA, protein, or catalytic activity levels. Upon co-exposure to V(5+) and TCDD, V(5+) significantly potentiated the TCDD-mediated induction of the Cyp1a1, Cyp1a2, and Cyp1b1 mRNA, protein, and catalytic activity levels at 24 h. In vitro, V(5+) decreased the TCDD-mediated induction of Cyp1a1 mRNA, protein, and catalytic activity levels. Furthermore, V(5+) significantly inhibited the TCDD-induced AhR-dependent luciferase activity. V(5+) also increased serum hemoglobin (Hb) levels in animals treated for 24 h. Upon treatment of isolated hepatocytes with Hb alone or in the presence of TCDD, there was an increase in the AhR-dependent luciferase activity. When isolated hepatocytes were treated for 2 h with V(5+) in the presence of TCDD, followed by replacement of the medium with new medium containing Hb, there was further potentiation to the TCDD-mediated effect. The present study demonstrates that there is a differential modulation of Cyp1a1 by V(5+) in C57BL/6 mice livers and isolated hepatocytes and demonstrates Hb as an in vivo specific modulator.

Issa Emhemmed Alemyani Amara, (08-2013), Archives of Toxicology: SPRINGER LINK, 87

Posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by methylmercury in HepG2 cells: a role of heme oxygenase-1
Journal Article

Recently we demonstrated the ability of mercuric chloride (Hg(2+)) in human hepatoma HepG2 cells to significantly decrease the TCDD-mediated induction of Cytochrome P450 1A1 (CYP1A1) mRNA, protein, and catalytic activity levels. In this study we investigated the effect of methylmercury (MeHg) on CYP1A1 in HepG2 cells. For this purpose, cells were co-exposed to MeHg and TCDD and the expression of CYP1A1 mRNA, protein, and catalytic activity levels were determined. Our results showed that MeHg did not alter the TCDD-mediated induction of CYP1A1 mRNA, or protein levels; however it was able to significantly decrease CYP1A1 catalytic activity levels in a concentration-dependent manner. Importantly, this inhibition was specific to CYP1A1and was not radiated to other aryl hydrocarbon receptor (AhR)-regulated genes, as MeHg induced NAD(P)H:quinone oxidoreductase 1 mRNA and protein levels. Mechanistically, the inhibitory effect of MeHg on the induction of CYP1A1 coincided with an increase in heme oxygenase-1 (HO-1) mRNA levels. Furthermore, the inhibition of HO-1 activity, by tin mesoporphyrin, caused a complete restoration of MeHg-mediated inhibition of CYP1A1 activity, induced by TCDD. In addition, transfection of HepG2 cells with siRNA targeting the human HO-1 gene reversed the MeHg-mediated inhibition of TCDD-induced CYP1A1. In conclusion, this study demonstrated that MeHg inhibited the TCDD-mediated induction of CYP1A1 through a posttranslational mechanism and confirms the role of HO-1 in a MeHg-mediated effect.

Issa Emhemmed Alemyani Amara, (06-2013), Toxicology Letters: Elsevier, 219

Differential modulation of cytochrome P450 1a1 by arsenite in vivo and in vitro in C57BL/6 mice
Journal Article

Heavy metals, typified by arsenite (As(III)), have been implicated in altering the carcinogenicity of aryl hydrocarbon receptor (AhR) ligands, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), by modulating the induction of the Cyp1a1 enzyme, but the mechanism remains unresolved. In this study, the effects of As(III) on Cyp1a1 expression and activity were investigated in C57BL/6 mouse livers and isolated hepatocytes. For this purpose, C57BL/6 mice were injected intraperitoneally with As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) for 6 and 24 h. Furthermore, isolated hepatocytes from C57BL/6 mice were treated with As(III) (1, 5, and 10 μM) in the absence and presence of TCDD (1 nM) for 3, 6, 12, and 24 h. At the in vivo level, As(III) decreased the TCDD-mediated induction of Cyp1a1 mRNA at 6h while potentiating its mRNA, protein, and catalytic activity levels at 24 h. At the in vitro level, As(III) decreased the TCDD-mediated induction of Cyp1a1 mRNA in a concentration- and time-dependent manner. Moreover, As(III) decreased the TCDD-mediated induction of Cyp1a1 protein and catalytic activity levels at 24 h. Interestingly, As(III) increased the serum hemoglobin (Hb) levels in animals treated for 24 h. Upon treatment of isolated hepatocytes with Hb alone, there was an increase in the nuclear accumulation of AhR and AhR-dependent luciferase activity. Furthermore, Hb potentiated the TCDD-induced AhR-dependent luciferase activity. Importantly, when isolated hepatocytes were treated for 5h with As(III) in the presence of TCDD and the medium was then replaced with new medium containing Hb, there was potentiation of the TCDD-mediated effect. Taken together, these results demonstrate for the first time that there is a differential modulation of the TCDD-mediated induction of Cyp1a1 by As(III) in C57BL/6 mouse livers and isolated hepatocytes. Thus, this study implicates Hb as an in vivo-specific modulator.

Issa Emhemmed Alemyani Amara, (05-2013), Free Radical Biology and Medicine: Elsevier, 58

Mercury modulates the cytochrome P450 1a1, 1a2 and 1b1 in C57BL/6J mice: in vivo and in vitro studies, Toxicol
Journal Article

In the current study C57BL/6J mice were injected intraperitoneally with Hg(2+) in the absence and presence of TCDD. After 6 and 24h the liver was harvested and the expression of Cyps was determined. In vitro, isolated hepatocytes were incubated with TCDD in the presence and absence of Hg(2+). At the in vivo level, Hg(2+) significantly decreased the TCDD-mediated induction of Cyps at 6h while potentiating their levels at 24h. In vitro, Hg(2+) significantly inhibited the TCDD-mediated induction of Cyp1a1 in a concentration- and time-dependent manner. Interestingly, Hg(2+) increased the serum hemoglobin (Hb) levels in mice treated for 24h. Upon treatment of isolated hepatocytes with Hb alone, there was an increase in the AhR-dependent luciferase activity with a subsequent increase in Cyp1a1 protein and catalytic activity levels. Importantly, when hepatocytes were treated for 2h with Hg(2+) in the presence of TCDD, then the medium was replaced with new medium containing Hb, there was potentiation of the TCDD-mediated effect. In addition, Hg(2+) increased heme oxygenase-1 (HO-1) mRNA, which coincided with a decrease in the Cyp1a1 activity level. When the competitive HO-1 inhibitor, tin mesoporphyrin was applied to the hepatocytes there was a partial restoration of Hg(2+)-mediated inhibition of Cyp1a1 activity. In conclusion, we demonstrate for the first time that there is a differential modulation of the TCDD-mediated induction of Cyp1a1 by Hg(2+) in C57BL/6J mice livers and isolated hepatocytes. Moreover, this study implicates Hb as an in vivo specific modulator of Cyp1 family.

Issa Emhemmed Alemyani Amara, (02-2013), Toxicology and Applied Pharmacology: Elsevier, 266

Effect of Mercury on AhR-regulated genes in C57Bl/6 Mice at Different Extrahepatic Tissues
Journal Article

The individual toxic effects of aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by mercury (Hg(2+)) has been previously demonstrated. However, little is known about the combined toxic effects of TCDD and Hg(2+)in vivo. Therefore, we examined the effect of exposure to Hg(2+) (2.5mg/kg) in the absence and presence of TCDD (15 μg/kg) on the AhR-regulated genes using C57Bl/6 mice. Hg(2+) alone did not affect kidney, lung, or heart Cyp1a1/1a2/1b1 mRNA levels. On the contrary, Hg(2+) alone significantly induced kidney Cyp1a1/1a2/1b1 and lung Cyp1b1 protein and catalytic activities. Hg(2+) also induced Nqo1, Gsta1, and HO-1 at the mRNA, protein, and activity levels in the kidney and heart but not in the lung. Upon co-exposure to Hg(2+) and TCDD, Hg(2+) significantly potentiated the TCDD-mediated induction of kidney and lung Cyp1a1/1a2/1b1 mRNA levels, while it decreased their kidney protein and catalytic activity and it increased their lung protein. In addition, Hg(2+) potentiated the TCDD-mediated induction of Nqo1, Gsta1, and HO-1 at mRNA, protein and activity levels in all tissues. The present study demonstrates that Hg(2+) modulates the constitutive and TCDD-induced AhR-regulated genes in a time-, tissue- and, AhR-regulated enzyme genes manner.

Issa Emhemmed Alemyani Amara, (07-2012), Food and Chemical Toxicology: Elsevier, 50

Differential modulation of aryl hydrocarbon receptor regulated genes by arsenite in the kidney, lung, and heart of C57BL/6 mice
Journal Article

During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR-regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) on the AhR-regulated genes using C57Bl/6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tissues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD-mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In conclusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD-induced AhR-regulated genes in a time-, tissue-, and AhR-regulated enzyme-specific manner.

Issa Emhemmed Alemyani Amara, (06-2012), Archives of Toxicology: SPRINGER LINK, 68

Modulation of Aryl Hydrocarbon Receptor-Regulated Genes by Acute Administration of Ammonium Metavanadate in an Extrahepatic Tissue of C57BL/6 Mouse
Journal Article

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 V5+ (5 mg kg−1) with or without TCDD (15 µg kg−1) on the AhR-regulated genes in kidney, lung and heart of C57BL/6 J mice. Our results demonstrated that V5+ alone significantly decreased Cyp1b1 protein and catalytic activity levels in kidney at 24 h. Moreover, it significantly potentiated Nqo1 and Gsta1 gene expression in the heart, and only Gsta1 gene expression in the lung. Upon co-exposure, we found that V5+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, V5+ 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 significantly potentiated at 6 h. Interestingly, all tested genes in the heart were significantly decreased at 6 h with the exception of Gsta1 mRNA. The present study demonstrates that V5+ modulates TCDD-induced AhR-regulated genes. Furthermore, the effect on one of these enzymes could not be generalized to other enzymes even if it was in the same organ.

Issa Emhemmed Alemyani Amara, (05-2012), Journal of Applied Toxicology: WILEY analytical Sciences, 33

Transcriptional Modulation of the NAD(P)H:quinone oxidoreductase 1 by Mercury in Human Hepatoma HepG2 Cells
Journal Article

NAD(P)H:quinone oxidoreductase (NQO1)-mediated detoxification of quinones plays a critical role in cancer prevention. Heavy metals such as mercury (Hg(2+)) alter the carcinogenicity of aryl hydrocarbon receptor ligands, mainly by modifying various xenobiotic-metabolizing enzymes such as NQO1. Therefore, we examined the effect of Hg(2+) on the expression of NQO1 in human hepatoma HepG2 cells. For this purpose HepG2 cells were incubated with various concentrations of Hg(2+) (2.5, 5, and 10μM) in the presence and absence of two NQO1 inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and isothiocyanate sulforaphane (SUL), as bifunctional and monofunctional inducers, respectively. Analysis of the time-dependent effect of Hg(2+) revealed that Hg(2+) increased the expression of NQO1 mRNA in a time-dependent manner. In addition, Hg(2+) increased NQO1 at the mRNA, protein, and activity levels in the presence and absence of both NQO1 inducers, TCDD and SUL, which coincided with increased nuclear accumulation of Nrf2 protein. Investigating the effect of Hg(2+) at the transcriptional level revealed that Hg(2+) significantly induced the antioxidant-responsive element-dependent luciferase reporter gene expression in the absence and the presence of both NQO1 inducers. NQO1 mRNA and protein decay experiments revealed a lack of posttranscriptional and posttranslational mechanisms. Transfecting HepG2 cells with siRNA for Nrf2 significantly decreased the Hg(2+)-mediated induction of NQO1 mRNA and catalytic activity by approximately 90%. In conclusion, we demonstrated that Hg(2+) regulates the expression of the NQO1 gene through a transcriptional mechanism in human hepatoma HepG2 cells. In addition, Nrf2 is involved in the modulation of NQO1 by Hg(2+).

Issa Emhemmed Alemyani Amara, (11-2011), Free Radical Biology and Medicine: Elsevier, 51

Mercury Modulates the CYP1A1 at Transcriptional and Posttranslational levels in Human Hepatoma HepG2 Cells
Journal Article

Aryl hydrocarbon receptor (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and metals, such as mercury (Hg(2+)), are environmental co-contaminants and their molecular interaction may disrupt the coordinated regulation of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1). Therefore, we examined the effect of co-exposure to Hg(2+) and TCDD on the expression of the CYP1A1 in HepG2 cells. Our results showed that Hg(2+) significantly inhibited the TCDD-mediated induction of CYP1A1 at the mRNA, protein, and catalytic activity levels. At the transcriptional level, co-exposure to Hg(2+) and TCDD significantly decreased the TCDD-mediated induction of AhR-dependent luciferase reporter gene expression. Moreover, Hg(2+) did not affect CYP1A1 mRNA stability, while decreasing its protein half-life, suggesting the involvement of a posttranslational mechanism. Importantly, Hg(2+) increased the expression of heme oxygenase-1 (HO-1), a rate limiting enzyme in heme degradation, which coincided with further decrease in the CYP1A1 catalytic activity levels. Upon using a competitive HO-1 inhibitor, tin mesoporphyrin, heme precursor, hemin, or transfecting the HepG2 cells with siRNA for HO-1 there was a partial restoration of the inhibition of TCDD-mediated induction of CYP1A1 catalytic activity. In conclusion, we demonstrate that Hg(2+) down-regulates the expression of CYP1A1 at the transcriptional and posttranslational levels in HepG2 cells. In addition, HO-1 is involved in the modulation of CYP1A1 at the posttranslational level.

Issa Emhemmed Alemyani Amara, (12-2010), Toxicology Letters: Elsevier, 199

Effect of Nifedipine on Alprazolam-induced Anxiolysis and Brain GABA Level Changes in Albino Rats
Journal Article

Objective: The present study investigates the effects of alprazolam (ALP) and nifedipine alone or in combination on behavior and on g-aminobutyric acid (GABA) levels, in discrete brain regions of albino rats.

Methods: The anxiolytic effect was studied using a plus maze model and brain levels of GABA were measured using high performance liquid chromatography. Four acute treatment groups of rats were used. In the first they were treated with 1% Tween 80 (1ml/kg), in the second with nifedipine (10mg/kg), in the third with ALP (2mg/kg) and in the fourth with ALP in addition to nifedipine in the respective doses. The work was carried out at the Faculty of Pharmacy of Al-Fateh University, Tripoli, Libya in the first half of 2002.

Results: The results indicate that the anxiolytic effect of ALP was not modified by nifedipine. Nifedipine by itself significantly decreased the motor activity (decrease in total lines crossed), this effect was apparently antagonized by ALP. Alprazolam administration produced an increase of GABA levels in cerebellum and striatum and a decrease in the brain stem. Nifedipine per-se had no effect on GABA levels in the brain stem but it partially antagonized ALP-induced inhibitory effect on GABA in this region. Alprazolam significantly increased GABA levels in the striatum, while nifedipine alone had no effect on neurotransmitter levels and did not modify the ALP effect in this brain region. Alprazolam or nifedipine had no significant effect on GABA levels in midbrain, cerebral cortex and whole brain. There were no significant changes in GABA levels in midbrain and whole brain with drug combination. However, the combination decreased GABA levels significantly in the cerebral cortex.

Conclusion: It may be concluded that, the anxiolytic effect of ALP possibly occurs through changes in brain GABA levels (an increase in cerebellum and striatum with a decrease in brain stem). The effect was not modified by nifedipine which per se had no affect on GABA levels in any brain area. The significant decrease in GABA levels in cerebral cortex by ALP-nifedipine combination may be due to the mutual closure of calcium channel (mentioned in literature) resulting in inhibition of the EAA-ergic input to GABA-ergic neuron.

Issa Emhemmed Alemyani Amara, (04-2003), المؤتمر الثالث للعلوم الصيدلانية أ سيوط / مصر: Neurosciences Journal , Riyadh KSA, 2