The Experts below are selected from a list of 216 Experts worldwide ranked by ideXlab platform
Kenneth W Renton - One of the best experts on this subject based on the ideXlab platform.
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Cytochrome P450 regulation and Drug Biotransformation during inflammation and infection.
Current drug metabolism, 2004Co-Authors: Kenneth W RentonAbstract:The expression of cytochrome P450 and related Biotransformation is altered during the operation of host defense mechanisms. This has major implications in inflammation and infection when the capacity of the liver and other organs to handle Drugs is severely compromised. In most cases individual cytochrome P450 forms are down regulated at the level of gene transcription with a resulting decrease in the corresponding mRNA, protein and enzyme activity. The loss in Drug metabolism is channeled predominantly through the production of cytokines which ultimately modify specific transcription factors. Other proposed mechanisms that apply to specific cytochrome P450s involve post translational steps including enzyme modification and increased degradation. When inflammatory responses are confined to the brain there is a loss of cytochrome P450 not only in the brain but also in peripheral tissues. This involves a yet to be identified mode of signaling between the brain and periphery but it does involve the production of cytokines from a peripheral source. In clinical medicine there are numerous examples of a decreased capacity to handle Drugs during infections and disease states that involve an inflammatory component. This often results in altered Drug responses and increased toxicities. Inflammation mediated alterations in the metabolism of endogenous compounds can lead to altered physiology. Changes in Drug handling capacity during inflammation/infection will continue to be one of the many factors that complicate therapeutics.
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Hepatic Drug metabolism and immunostimulation
Toxicology, 2000Co-Authors: Kenneth W RentonAbstract:When host defence mechanisms are stimulated there is a concomitant decrease in cytochrome P450 based Drug Biotransformation and elimination. This has resulted in a number of clinically important unwanted Drug responses in patients with infections or inflammatory responses. The loss in cytochrome P450 is predominantly an effect at the level of the gene expression and the majority of enzyme forms examined to date are involved. Although the effect occurs predominantly in the liver it has been recently shown that inflammatory responses in the brain also cause a loss of the same enzyme forms in that organ. The loss of cytochrome P450 in the brain in response to localised inflammation is accompanied by a similar loss in the liver. The decrease of cytochrome P450 and its dependent Drug Biotransformation is of concern whenever Drugs are used in patients with infections or disease states with an inflammatory component.
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Amlodipine Inhibits Rat Microsomal Cytochrome P450-Mediated Drug Biotransformation
Journal of pharmaceutical sciences, 1997Co-Authors: Robert K. Drobitch, Roman A. Mclellan, Kenneth W RentonAbstract:Calcium channel antagonists have been shown to inhibit cytochrome P-450-mediated metabolism both in vitro and in vivo. The purpose of the present study was to examine the effect of amlodipine on a suite of rat hepatic microsomal cytochrome P-450 activities to determine the potential for Drug interactions. In this study, amlodipine (0.05 and 0.5 mM) decreased CYP1A-mediated ethoxyresorufin O-deethylase activity in microsomes prepared from noninduced (56 and 73% inhibition) and pyridine-induced (30 and 51% inhibition) rats. Amlodipine reduced pentoxyresorufin O-deethylase activity (a marker for CYP2B) to 15% of control in incubations utilizing microsomes from phenobarbital-treated rats, but had no effect on this enzyme reaction in noninduced microsomes. The para-nitrophenol hydroxylase, erythromycin N-demethylase, and lauric acid omega and omega-1 hydroxylase activities were significantly inhibited by 1 mM amlodipine in both noninduced and induced microsomes. These results suggest that amlodipine inhibits a number of different P450 forms and therefore has the potential to inhibit the metabolism of a large number of Drugs.
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The effect of IFN-α-CON1 on hepatic cytochrome P-450 and protein synthesis and degradation in hepatic microsomes
International journal of immunopharmacology, 1991Co-Authors: Shabbir Moochhala, Kenneth W RentonAbstract:Interferon and its inducers are well known to depress Drug Biotransformation in the liver by decreasing the levels of cytochrome P-450 in that organ. We now report that IFN-alpha-Con1, which was constructed from the most frequently observed amino acid sequences in human alpha-interferon subtypes, causes a loss in cytochrome P-450 which could be prevented by pretreating animals with either puromycin or actinomycin D. This suggests that the loss in Drug Biotransformation is mediated via the production of an intermediate protein. When the turnover of microsomal protein was examined this interferon appeared to depress the synthesis of proteins with molecular weights 46-60 kd and had little effect on the synthesis of other proteins. The in vitro translation of proteins of molecular weights 45-60 kd was also depressed in an in vitro translation system using mRNA isolated from the livers of interferon treated hamsters. Interferon had no effect on the degradation of microsomal proteins of all molecular weights. It is concluded that interferon probably depresses the levels of cytochrome P-450 in the liver by decreasing the synthesis of the apoprotein and that interferon has little effect on the degradation of the hemoprotein.
Chantale Simard - One of the best experts on this subject based on the ideXlab platform.
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the guinea pig expresses functional cyp2c and p glycoprotein further validation of its usefulness in Drug Biotransformation transport studies
Biopharmaceutics & Drug Disposition, 2015Co-Authors: Ibrahim Hasibu, Dany Patoine, Sylvie Pilote, Benoit Drolet, Chantale SimardAbstract:Background: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of Drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C Drug-metabolizing enzyme and the P-glycoprotein (P-gp) Drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific Drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated Biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. Conclusion: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in Drug Biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.
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The guinea-pig expresses functional CYP2C and P-glycoprotein: further validation of its usefulness in Drug Biotransformation/transport studies
Biopharmaceutics & drug disposition, 2015Co-Authors: Ibrahim Hasibu, Dany Patoine, Sylvie Pilote, Benoit Drolet, Chantale SimardAbstract:Background: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of Drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C Drug-metabolizing enzyme and the P-glycoprotein (P-gp) Drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific Drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated Biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. Conclusion: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in Drug Biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.
Ibrahim Hasibu - One of the best experts on this subject based on the ideXlab platform.
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the guinea pig expresses functional cyp2c and p glycoprotein further validation of its usefulness in Drug Biotransformation transport studies
Biopharmaceutics & Drug Disposition, 2015Co-Authors: Ibrahim Hasibu, Dany Patoine, Sylvie Pilote, Benoit Drolet, Chantale SimardAbstract:Background: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of Drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C Drug-metabolizing enzyme and the P-glycoprotein (P-gp) Drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific Drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated Biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. Conclusion: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in Drug Biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.
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The guinea-pig expresses functional CYP2C and P-glycoprotein: further validation of its usefulness in Drug Biotransformation/transport studies
Biopharmaceutics & drug disposition, 2015Co-Authors: Ibrahim Hasibu, Dany Patoine, Sylvie Pilote, Benoit Drolet, Chantale SimardAbstract:Background: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of Drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C Drug-metabolizing enzyme and the P-glycoprotein (P-gp) Drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific Drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated Biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. Conclusion: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in Drug Biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.
Mary Vore - One of the best experts on this subject based on the ideXlab platform.
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hormonal regulation of hepatic Drug Biotransformation and transport systems
Comprehensive Physiology, 2013Co-Authors: Maria Laura Ruiz, Aldo D Mottino, Viviana Alicia Catania, Mary VoreAbstract:The human body is constantly exposed to many xenobiotics including environmental pollutants, food additives, therapeutic Drugs, etc. The liver is considered the primary site for Drug metabolism and elimination pathways, consisting in uptake, phase I and II reactions, and efflux processes, usually acting in this same order. Modulation of Biotransformation and disposition of Drugs of clinical application has important therapeutic and toxicological implications. We here provide a compilation and analysis of relevant, more recent literature reporting hormonal regulation of hepatic Drug Biotransformation and transport systems. We provide additional information on the effect of hormones that tentatively explain differences between sexes. A brief discussion on discrepancies between experimental models and species, as well as a link between gender-related differences and the hormonal mechanism explaining such differences, is also presented. Finally, we include a comment on the pathophysiological, toxicological, and pharmacological relevance of these regulations. © 2013 American Physiological Society. Compr Physiol 3:1721-1740, 2013.
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Comprehensive Physiology - Hormonal Regulation of Hepatic Drug Biotransformation and Transport Systems
Comprehensive Physiology, 2013Co-Authors: Maria Laura Ruiz, Aldo D Mottino, Viviana Alicia Catania, Mary VoreAbstract:The human body is constantly exposed to many xenobiotics including environmental pollutants, food additives, therapeutic Drugs, etc. The liver is considered the primary site for Drug metabolism and elimination pathways, consisting in uptake, phase I and II reactions, and efflux processes, usually acting in this same order. Modulation of Biotransformation and disposition of Drugs of clinical application has important therapeutic and toxicological implications. We here provide a compilation and analysis of relevant, more recent literature reporting hormonal regulation of hepatic Drug Biotransformation and transport systems. We provide additional information on the effect of hormones that tentatively explain differences between sexes. A brief discussion on discrepancies between experimental models and species, as well as a link between gender-related differences and the hormonal mechanism explaining such differences, is also presented. Finally, we include a comment on the pathophysiological, toxicological, and pharmacological relevance of these regulations. © 2013 American Physiological Society. Compr Physiol 3:1721-1740, 2013.
Benoit Drolet - One of the best experts on this subject based on the ideXlab platform.
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the guinea pig expresses functional cyp2c and p glycoprotein further validation of its usefulness in Drug Biotransformation transport studies
Biopharmaceutics & Drug Disposition, 2015Co-Authors: Ibrahim Hasibu, Dany Patoine, Sylvie Pilote, Benoit Drolet, Chantale SimardAbstract:Background: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of Drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C Drug-metabolizing enzyme and the P-glycoprotein (P-gp) Drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific Drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated Biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. Conclusion: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in Drug Biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.
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The guinea-pig expresses functional CYP2C and P-glycoprotein: further validation of its usefulness in Drug Biotransformation/transport studies
Biopharmaceutics & drug disposition, 2015Co-Authors: Ibrahim Hasibu, Dany Patoine, Sylvie Pilote, Benoit Drolet, Chantale SimardAbstract:Background: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of Drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. Objective: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C Drug-metabolizing enzyme and the P-glycoprotein (P-gp) Drug transporter in various tissues. Methods: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific Drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Results: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated Biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. Conclusion: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in Drug Biotransformation/transport studies. Copyright © 2015 John Wiley & Sons, Ltd.
