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1.
Curr Drug Metab ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38752643

RESUMEN

BACKGROUND: Cathinone is a natural stimulant found in the Catha edulis plant. Its derivatives make up the largest group of new psychoactive substances. In order to better understand its effects, it is imperative to investigate its distribution, pharmacokinetics, and metabolic profile. However, the existing literature on cathinone remains limited. OBJECTIVE: This study aimed to investigate the disposition kinetics and metabolic profile of cathinone and its metabolite cathine through a single oral dose of cathinone administration in rats. METHODS: Cathinone and cathine concentrations were identified and quantified using ion trap liquid chromatography- mass spectrometry (LC-IT/MS). The metabolic profile in the serum, brain, lung, liver, kidney, and heart was analyzed at specific time points (0, 0.5, 2.5, 6, 12, 24, 48, and 72 hours) using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method. RESULTS: The highest concentration of cathinone was found in the kidney (1438.6 µg/L, which gradually decreased to 1.97 within 48 h and disappeared after 72 h. Cathinone levels in the lungs, liver, and heart were 859, 798.9, and 385.8 µg/L, respectively, within half an hour. However, within 2.5 hours, these levels decreased to 608.1, 429.3, and 309.1 µg/L and became undetectable after 24 h. In the rat brain, cathinone levels dropped quickly and were undetectable within six hours, decreasing from 712.7 µg/L after 30 min. In the brain and serum, cathine reached its highest levels at 2.5 hours, while in other organs, it peaked at 0.5 hours, indicating slower conversion of cathinone to cathine in the brain and serum. CONCLUSION: This study revealed a dynamic interplay between cathinone disposition kinetics and its impact on organ-specific metabolic profiles in rats. These results have significant implications for drug development, pharmacovigilance, and clinical practices involving cathinone. Investigating the correlation between the changes in biomarkers found in the brain and the levels of cathinone and cathine is essential for informed decision- making in medical practices and further research into the pharmacological properties of cathinone.

2.
Toxics ; 11(6)2023 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-37368606

RESUMEN

Interpreting fatalities involving khat is challenging due to a lack of data on cathinone and cathine reference concentrations in postmortem tissues. This study investigated the autopsy findings and toxicological results of fatalities involving khat in Saudi Arabia's Jazan region from 1 January 2018 to 31 December 2021. All confirmed cathine and cathinone results in postmortem blood, urine, brain, liver, kidney, and stomach samples were recorded and analyzed. Autopsy findings and the manner and cause of death of the deceased were assessed. Saudi Arabia's Forensic Medicine Center investigated 651 fatality cases over four years. Thirty postmortem samples were positive for khat's active constituents, cathinone and cathine. The percentage of fatalities involving khat was 3% in 2018 and 2019 and increased from 4% in 2020 to 9% in 2021, when compared with all fatal cases. They were all males ranging in age from 23 to 45. Firearm injuries (10 cases), hanging (7 cases), road traffic accident (2 cases), head injury (2 cases), stab wounds (2 cases), poisoning (2 cases), unknown (2 cases), ischemic heart disease (1 case), brain tumor (1 case), and choking (1 case) were responsible for the deaths. In total, 57% of the postmortem samples tested positive for khat only, while 43% tested positive for khat with other drugs. Amphetamine is the drug most frequently involved. The average cathinone and cathine concentrations were 85 and 486 ng/mL in the blood, 69 and 682 ng/mL in the brain, 64 and 635 ng/mL in the liver, and 43 and 758 ng/mL in the kidneys, respectively. The 10th-90th percentiles of blood concentrations of cathinone and cathine were 18-218 ng/mL and 222-843 ng/mL, respectively. These findings show that 90% of fatalities involving khat had cathinone concentrations greater than 18 ng/mL and cathine concentrations greater than 222 ng/mL. According to the cause of death, homicide was the most common fatality involving khat alone (77%). More research is required, especially toxicological and autopsy findings, to determine the involvement of khat in crimes and fatalities. This study may help forensic scientists and toxicologists investigate fatalities involving khat.

3.
Molecules ; 28(12)2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37375342

RESUMEN

Amphetamine is a psychostimulant drug with a high risk of toxicity and death when misused. Abuse of amphetamines is associated with an altered organic profile, which includes omega fatty acids. Low omega fatty acid levels are linked to mental disorders. Using the Comparative Toxicogenomic Database (CTD), we investigated the chemical profile of the brain in amphetamine-related fatalities and the possibility of neurotoxicity. We classified amphetamine cases as low (0-0.5 g/mL), medium (>0.5 to 1.5 g/mL), and high (>1.5 g/mL), based on amphetamine levels in brain samples. All three groups shared 1-octadecene, 1-tridecene, 2,4-di-tert-butylphenol, arachidonic acid (AA), docosahexaenoic acid (DHA), eicosane, and oleylamide. We identified chemical-disease associations using the CTD tools and predicted an association between DHA, AA and curated conditions like autistic disorder, disorders related to cocaine, Alzheimer's disease, and cognitive dysfunction. An amphetamine challenge may cause neurotoxicity in the human brain due to a decrease in omega-3 fatty acids and an increase in oxidative products. Therefore, in cases of amphetamine toxicity, a supplement therapy may be needed to prevent omega-3 fatty acid deficiency.


Asunto(s)
Anfetamina , Ácidos Grasos Omega-3 , Humanos , Anfetamina/efectos adversos , Toxicogenética , Encéfalo , Ácidos Docosahexaenoicos , Ácido Araquidónico
4.
Drug Metab Pers Ther ; 38(2): 199-207, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36883753

RESUMEN

OBJECTIVES: Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. METHODS: Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. RESULTS: The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. CONCLUSIONS: Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest Cmax in the lung and Tmax in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.


Asunto(s)
Catha , Dopamina , Ratas , Animales , Catha/química , Cinética , Serotonina , Ratas Wistar , Extractos Vegetales/farmacología , Norepinefrina , Epinefrina
6.
Environ Sci Pollut Res Int ; 29(43): 64959-64970, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35482242

RESUMEN

Lead (Pb) is one of the most frequent hazardous air contaminants, where the lungs are particularly vulnerable to its toxicity. However, the Pb distribution and its impact on lung inflammation/apoptosis and particularly the involvement of nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways in Pb-induced lung toxicity have not yet been fully investigated. Adult male Wistar albino rats were exposed to Pb nitrate 25, 50, and 100 mg/kg b.w. orally for 3 days. The histopathological changes of several rat organs were analyzed using hematoxylin and eosin staining. The concentrations of Pb ion in different organ tissues were quantified using inductive coupled plasma mass spectrometry, while gas chromatography-mass spectrometry was used to identify organic compounds. The changes in the mRNA and protein expression levels of inflammatory and apoptotic genes in response to Pb exposure were quantified by using RT-PCR and Western blot analyses, respectively. Treatment of rats with Pb for three consecutive days significantly increased the accumulation of Pb in lung tissues causing severe interstitial inflammation. Pb treatment also increased the percentage of lung apoptotic cells and modulated apoptotic genes (Bc2, p53, and TGF-α), inflammatory markers (IL-4, IL-10, TNF-α), and oxidative stress biomarkers (iNOS, CYP1A1, EphX) in rat lung tissues. These effects were associated with a significant increase in organic compounds, such as 3-nitrotyrosine and myeloperoxidase, and some inorganic elements, such as selenium. Importantly, the Pb-induced lung inflammation and apoptosis were associated with a proportional increase in the expression of NF-κB and AhR mRNAs and proteins. These findings clearly show that Pb induces severe inflammation and apoptosis in rat lungs and suggest that NF-κB and AhR may play a role in Pb-induced lung toxicity.


Asunto(s)
Apoptosis , Neumonía , Receptores de Hidrocarburo de Aril , Animales , Inflamación/inducido químicamente , Inflamación/metabolismo , Plomo/farmacología , Pulmón , Masculino , FN-kappa B/metabolismo , Nitratos/farmacología , Neumonía/metabolismo , Ratas , Ratas Wistar , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal
7.
Drug Metab Pers Ther ; 36(4): 295-298, 2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-34821129

RESUMEN

OBJECTIVES: Khat (Catha edulis) is a stimulant plant, and it is abusive to induce euphoria, alertness and activity. Concomitant use of medications and khat chewing predisposes to the appearance of drug interactions result in treatment failure or toxicity. This study determined the changes in the urinary inorganic profile in adult healthy males who are chewing khat compared with non-khat chewer males. METHODS: A total of 40 adult non-smoker healthy males (20 khat chewer and 20 non-khat chewer) aged 24-30 years were selected. Khat chewer samples were positive for cathinone and cathine and negative for other drug of abuse, while non-khat chewer samples were negative for drug of abuse include cathinone and cathine. Samples were selected according to their results in immunoassay and gas chromatography mass spectrometry (GCMS) analysis. Cathine and cathinone were confirmed using liquid chromatography mass spectrometry (LC-MSMS) analysis. Inorganic profile includes titanium (Ti), cobalt (Co), copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) were determined by using inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The levels of Ti, Co, Zn, Cd, and Pb in urine were significantly higher among the khat chewer group compared with non-khat chewer. Ti, Cd, Co, Pb and Zn urine levels were 0.5-, 1.5-, 1.15-, 5-, and 8.2-fold higher in the khat chewer group compared to non-khat chewer, respectively. CONCLUSIONS: We suggested that continuous khat chewing has a long term effect on metabolic pathway of therapeutic drugs that result in toxicity or failure of therapy.


Asunto(s)
Catha , Masticación , Adulto , Catha/efectos adversos , Catha/química , Cromatografía Liquida , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Adulto Joven
8.
Drug Metab Pers Ther ; 2021 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-33951761

RESUMEN

OBJECTIVES: Khat (Catha edulis) is a stimulant plant, and it is abusive to induce euphoria, alertness and activity. Concomitant use of medications and khat chewing predisposes to the appearance of drug interactions result in treatment failure or toxicity. This study determined the changes in the urinary inorganic profile in adult healthy males who are chewing khat compared with non-khat chewer males. METHODS: A total of 40 adult non-smoker healthy males (20 khat chewer and 20 non-khat chewer) aged 24-30 years were selected. Khat chewer samples were positive for cathinone and cathine and negative for other drug of abuse, while non-khat chewer samples were negative for drug of abuse include cathinone and cathine. Samples were selected according to their results in immunoassay and gas chromatography mass spectrometry (GCMS) analysis. Cathine and cathinone were confirmed using liquid chromatography mass spectrometry (LC-MSMS) analysis. Inorganic profile includes titanium (Ti), cobalt (Co), copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) were determined by using inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The levels of Ti, Co, Zn, Cd, and Pb in urine were significantly higher among the khat chewer group compared with non-khat chewer. Ti, Cd, Co, Pb and Zn urine levels were 0.5-, 1.5-, 1.15-, 5-, and 8.2-fold higher in the khat chewer group compared to non-khat chewer, respectively. CONCLUSIONS: We suggested that continuous khat chewing has a long term effect on metabolic pathway of therapeutic drugs that result in toxicity or failure of therapy.

9.
Risk Manag Healthc Policy ; 13: 373-378, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32547271

RESUMEN

OBJECTIVE: This study examined the incidence of drug-related problems (DRPs) in different inpatient departments along with the medical team response to pharmacist's action in addressing DRPs at Jazan Hospital, Saudi Arabia. PATIENTS AND METHODS: This retrospective study was conducted among inpatients at Ministry of Health hospital in Jazan, a region in southwestern Saudi Arabia. We collected data for a 2-year period (from 2016 to 2017). For any detected DRP of the ordered medications for dispensing, the inpatient pharmacist is sending report for that particular DRP with recommendation to the medical team which in turn might accept or reject such recommendation. Serious drug-drug interactions, as part of DRP, were assessed by utilizing three different online DDI checkers, including Lexi-Comp, Medscape, and Drugs.com. RESULTS: The most common type of DRP was serious drug-drug interactions (49%). Over the study period, most incidences of DRPs were decreased. Of the DRPs in 2016 and 2017, antibiotics were the most commonly involved (51% and 69.5%) of cases, respectively, followed by proton pump inhibitors (25.3% and 14.1%) and statins (12.9% and 9.4%). Interestingly, of the 241 interventions for DRPs in 2016, 199 (82.5%) were accepted, resulting in a change in drug therapy (p=0.006). In 2017, 90 (70.3%) interventions out of 128 were accepted by the physician and the drug therapy changed (p=0.029). CONCLUSION: Pharmacist interventions appear to decrease the incidence of DRPs, which emphasize the importance of an optimal pharmaceutical care plan for clinical care settings.

10.
Drug Deliv ; 27(1): 622-631, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32329374

RESUMEN

NLC containing Gefitinib (NANOGEF) was prepared using stearic acid, sesame oil and surfactants (sodium lauryl sulfate and tween 80). NANOGEFs were evaluated for particle size, polydispersity index (PdI), zeta potential, entrapment efficiency (EE), stability, release studies and cytotoxicity studies (MTT assay). The optimized NANOGEF exhibited particle size of 74.06 ± 9.73 d.nm, PdI of 0.339 ± 0.029 and EE of 99.76 ± 0.015%. The TEM study revealed spherical shape of NANOGEF formulations. The slow and sustained release behavior was exhibited by all NANOGEFs. The effects of surfactants were observed not only on particle size but also on zeta potential, entrapment efficiency, stability and release studies. The MTT assay revealed 4.5 times increase in cytotoxicity for optimized NANOGEF (IC50 = 4.642 µM) when compared with Gefitinib alone (IC50 = 20.88 µM in HCT-116 cells). Thus NANOGEF may be considered as a potential drug delivery system for the cure of colon cancer.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Gefitinib/administración & dosificación , Lípidos/química , Nanoestructuras/química , Muerte Celular , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Células HCT116 , Humanos , Lípidos/administración & dosificación , Nanoestructuras/administración & dosificación , Tamaño de la Partícula
11.
Toxicol Mech Methods ; 30(3): 197-207, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31682781

RESUMEN

Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-κB and/or AhR pathways remains unclear. This study was established to explore the role of NF-κB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-κB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-κB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-κB and AhR-dependent mechanism.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Plomo/toxicidad , Pulmón/efectos de los fármacos , FN-kappa B/fisiología , Receptores de Hidrocarburo de Aril/fisiología , Células A549 , Apoptosis/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Humanos , Pulmón/metabolismo , Pulmón/patología , FN-kappa B/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Resveratrol/farmacología
12.
Onco Targets Ther ; 13: 13357-13370, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33414642

RESUMEN

INTRODUCTION: Venetoclax (VCX) is a selective BCL-2 inhibitor approved for the treatment of leukemia and lymphoma. However, the mechanisms of anti-cancer effect of VCX either as a monotherapy or in combination with other chemotherapeutic agents against breast cancer need investigation. METHODS: Breast cancer cell lines with different molecular subtypes (MDA-MB-231, MCF-7, and SKBR-3) were treated with different concentrations of VCX for indicated time points. The expression of cell proliferative, apoptotic, and autophagy genes was determined by qRT-PCR and Western blot analyses. In addition, the percentage of MDA-MB-231 cells underwent apoptosis, expressed higher oxidative stress levels, and the changes in the cell cycle phases were determined by flow cytometry. RESULTS: Treatment of human breast cancer cells with increasing concentrations of VCX caused a significant decrease in cells growth and proliferation. This effect was associated with a significant increase in the percentage of apoptotic MDA-MB-231 cells and in the expression of the apoptotic genes, caspase 3, caspase 7, and BAX, with inhibition of anti-apoptotic gene, BCL-2 levels. Induction of apoptosis by VCX treatment induced cell cycle arrest at G0/G1 phase with inhibition of cell proliferator genes, cyclin D1 and E2F1. Furthermore, VCX treatment increased the formation of reactive oxygen species and the expression level of autophagy markers, Beclin 1 and LC3-II. Importantly, these cellular changes by VCX increased the chemo-sensitivity of MDA-MB-231 cells to doxorubicin. DISCUSSION: The present study explores the molecular mechanisms of VCX-mediated inhibitory effects on the growth and proliferation of TNBC MDA-MB-231 cells through the induction of apoptosis, cell cycle arrest, and autophagy. The study also explores the role of BCL-2 as a novel targeted therapy for breast cancer.

13.
Toxicol Mech Methods ; 29(2): 119-127, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30273082

RESUMEN

Although a plethora of studies have examined tobacco smoke-cancer disease association, the involvement of cellular genetic toxicity remains unclear. Therefore, the present study provides molecular evidence for a pathway involved in the DNA damage induced by long-term cigarette and waterpipe smoke in human subjects. The study population consisted of 45 subjects who were divided into three groups; healthy nonsmokers group, cigarette smokers group, and waterpipe smokers group. A questionnaire and consent form was distributed and signed by all participants. Total RNA was extracted from the blood using PAXgene Blood RNA Kit and mRNA expression levels of target genes were quantified by RT-PCR. Our results showed that 80% of the participants smoke 20-39 cigarettes/day, whereas 12% smoke more than 40 cigarettes/day. With regard to waterpipe smoke, the majority (46%) smoke more than 5 times/week. Both cigarette and waterpipe smokers showed increased the plasma levels 8-hydroxy-2'-deoxyguanosine (8-OHdG), of DNA damage marker. In addition, the mRNA expression levels of DNA repair genes (OGG1 and XRCC1) were significantly inhibited in both cigarette and waterpipe smokers groups by 30% and 60%, respectively. This was associated with a marked decrease (50%) in the expression of detoxifying genes (NQO1 and GSTA1) with an increase in CYP1A1 mRNA expression, a cancer-activating gene. Both cigarette and waterpipe smokers increased in the plasma concentrations of several toxic heavy metals such as Cd (130%), Pb (47%), and Ni (30%). In conclusion: the present findings clearly explore the genotoxic effect of cigarette and waterpipe smoking on human DNA.


Asunto(s)
Fumar Cigarrillos/efectos adversos , Daño del ADN , Exposición por Inhalación/efectos adversos , Estrés Oxidativo , Humo/efectos adversos , Fumadores , Fumar en Pipa de Agua/efectos adversos , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Fumar Cigarrillos/sangre , Fumar Cigarrillos/genética , Citocromo P-450 CYP1A1/sangre , Citocromo P-450 CYP1A1/genética , ADN Glicosilasas/sangre , ADN Glicosilasas/genética , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangre , Femenino , Regulación Enzimológica de la Expresión Génica , Glutatión Transferasa/sangre , Glutatión Transferasa/genética , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , NAD(P)H Deshidrogenasa (Quinona)/sangre , NAD(P)H Deshidrogenasa (Quinona)/genética , Medición de Riesgo , Factores de Tiempo , Transcriptoma , Fumar en Pipa de Agua/sangre , Fumar en Pipa de Agua/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/sangre , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Adulto Joven
14.
Environ Pollut ; 221: 64-74, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27916491

RESUMEN

Heavy metals are the most commonly encountered toxic substances that increase susceptibility to various diseases after prolonged exposure. We have previously shown that healthy volunteers living near a mining area had significant contamination with heavy metals associated with significant changes in the expression of some detoxifying genes, xenobiotic metabolizing enzymes, and DNA repair genes. However, alterations of most of the molecular target genes associated with diseases are still unknown. Thus, the aims of this study were to (a) evaluate the gene expression profile and (b) identify the toxicities and potentially relevant human disease outcomes associated with long-term human exposure to environmental heavy metals in mining area using microarray analysis. For this purpose, 40 healthy male volunteers who were residents of a heavy metal-polluted area (Mahd Al-Dhahab city, Saudi Arabia) and 20 healthy male volunteers who were residents of a non-heavy metal-polluted area were included in the study. Total RNA was isolated from whole blood using PAXgene Blood RNA tubes and then reversed transcribed and hybridized to the gene array using the Affymetrix U219 GeneChip. Microarray analysis showed about 2129 genes were identified and differentially altered, among which a shared set of 425 genes was differentially expressed in the heavy metal-exposed groups. Ingenuity pathway analysis revealed that the most altered gene-regulated diseases in heavy metal-exposed groups included hematological and developmental disorders and mostly renal and urological diseases. Quantitative real-time polymerase chain reaction closely matched the microarray data for some genes tested. Importantly, changes in gene-related diseases were attributed to alterations in the genes encoded for protein synthesis. Renal and urological diseases were the diseases that were most frequently associated with the heavy metal-exposed group. Therefore, there is a need for further studies to validate these genes, which could be used as early biomarkers to prevent renal injury.


Asunto(s)
Exposición a Riesgos Ambientales/estadística & datos numéricos , Contaminantes Ambientales/toxicidad , Contaminación Ambiental/estadística & datos numéricos , Metales Pesados/toxicidad , Biomarcadores/metabolismo , Contaminantes Ambientales/metabolismo , Perfilación de la Expresión Génica , Humanos , Inactivación Metabólica/genética , Riñón/metabolismo , Masculino , Metales Pesados/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis por Matrices de Proteínas , Reacción en Cadena en Tiempo Real de la Polimerasa , Arabia Saudita , Transcriptoma
15.
Toxicol Lett ; 252: 50-61, 2016 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-27084042

RESUMEN

Gefitinib (GEF) is a multi-targeted tyrosine kinase inhibitor with anti-cancer properties, yet few cases of cardiotoxicity has been reported as a significant side effect associated with GEF treatment. The main purpose of this study was to investigate the potential cardiotoxic effect of GEF and the possible mechanisms involved using in vivo and in vitro rat cardiomyocyte model. Treatment of rat cardiomyocyte H9c2 cell line with GEF (0, 1, 5, and 10µM) caused cardiomyocyte death and upregulation of hypertrophic gene markers, such as brain natriuretic peptides (BNP) and Beta-myosin heavy chain (ß-MHC) in a concentration-dependent manner at the mRNA and protein levels associated with an increase in the percentage of hypertrophied cardiac cells. Mechanistically, GEF treatment caused proportional and concentration-dependent increases in the mRNA and protein expression levels of apoptotic markers caspase-3 and p53 which was accompanied with marked increases in the percentage of H9c2 cells underwent apoptosis/necrosis as compared to control. In addition, oxidative stress marker (heme oxygenase-1, HO-1) and the formation of reactive oxygen species were increased in response to GEF treatment. At the in vivo level, treatment of Wistar albino rats for 21days with GEF (20 and 30mg/kg) significantly increased the cardiac enzymes (CK, CKmb, and LDH) levels associated with histopathological changes indicative of cardiotoxicity. Similarly, in vivo GEF treatment increased the mRNA and protein levels of BNP and ß-MHC whereas inhibited the antihypertrophoic gene (α-MHC) associated with increased the percentage of hypertrophied cells. Furthermore, the mRNA and protein expression levels of caspase-3, p53, and HO-1 genes and the percentage of apoptotic cells were significantly increased by GEF treatment, which was more pronounced at the 30mg/kg dose. In conclusion, GEF induces cardiotoxicity and cardiac hypertrophy in vivo and in vitro rat model through cardiac apoptotic cell death and oxidative stress pathways.


Asunto(s)
Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Cardiomegalia/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Quinazolinas/toxicidad , Animales , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiotoxicidad , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Gefitinib , Regulación de la Expresión Génica/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/genética , Hemo Oxigenasa (Desciclizante)/metabolismo , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
16.
Basic Clin Pharmacol Toxicol ; 119(2): 173-83, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26797788

RESUMEN

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.


Asunto(s)
Indoles/farmacología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Pirroles/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Familia 2 del Citocromo P450/antagonistas & inhibidores , Familia 2 del Citocromo P450/genética , Familia 2 del Citocromo P450/metabolismo , Familia 4 del Citocromo P450/genética , Familia 4 del Citocromo P450/metabolismo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Riñón/enzimología , Peroxidación de Lípido/efectos de los fármacos , Hígado/enzimología , Masculino , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Esteroide 16-alfa-Hidroxilasa/antagonistas & inhibidores , Esteroide 16-alfa-Hidroxilasa/genética , Esteroide 16-alfa-Hidroxilasa/metabolismo , Sunitinib , Transcriptoma , Xenobióticos/metabolismo
17.
Environ Pollut ; 181: 226-32, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23872045

RESUMEN

The present study was designed to evaluate the influence of long-term environmental human exposure to three heavy metals, lead (Pb), cadmium (Cd), and mercury (Hg), on the expression of detoxifying, xenobiotic metabolizing, and DNA repair genes in Mahd Ad-Dahab city. The study groups consisted of 40 healthy male residents (heavy metal-exposed) and 20 healthy male from Riyadh city, 700 km away, and served as control group. The heavy metal-exposed group with high exposure to Pb, Cd, or Hg was divided into three subgroups Pb-, Cd-, and Hg-exposed groups, respectively. The mRNA expression levels of detoxifying, NQO1, HO-1, GSTA1, MT-1, and HSP70, were significantly decreased in all heavy metal-exposed group as compared to control group. This was accompanied with a proportional decrease in the expression of xenobiotic metabolizing gene, cytochrome P4501A1. On the other hand, the DNA repair gene OGG1 and the 8-OHdG level were dramatically inhibited in Cd-exposed group only.


Asunto(s)
Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/toxicidad , Inactivación Metabólica/genética , Metales Pesados/toxicidad , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Reparación del ADN/efectos de los fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/genética , Desoxiguanosina/metabolismo , Exposición a Riesgos Ambientales/estadística & datos numéricos , Contaminantes Ambientales/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/genética , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/metabolismo , Proteínas del Choque Térmico HSP72/genética , Proteínas del Choque Térmico HSP72/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Metales Pesados/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , ARN Mensajero/metabolismo , Adulto Joven
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