Effect of experimental kidney disease on the functional expression of hepatic reductases.
Identifieur interne : 000527 ( Main/Exploration ); précédent : 000526; suivant : 000528Effect of experimental kidney disease on the functional expression of hepatic reductases.
Auteurs : Osama Y. Alshogran [Canada] ; Judith Naud [Canada] ; Andrew J. Ocque [Canada] ; François A. Leblond [Canada] ; Vincent Pichette [Canada] ; Thomas D. Nolin [États-Unis]Source :
- Drug metabolism and disposition: the biological fate of chemicals [ 1521-009X ] ; 2015.
Descripteurs français
- KwdFr :
- 11-beta-Hydroxysteroid dehydrogenase type 1 (métabolisme), Alcohol oxidoreductases (métabolisme), Aldose reductase (métabolisme), Animaux, Cytosol (enzymologie), Cytosol (métabolisme), Foie (enzymologie), Foie (métabolisme), Maladies du rein (enzymologie), Maladies du rein (métabolisme), Microsomes du foie (enzymologie), Microsomes du foie (métabolisme), Modèles animaux de maladie humaine, Mâle, Oxidoreductases (métabolisme), Rat Sprague-Dawley, Rats, Warfarine (métabolisme).
- MESH :
- enzymologie : Cytosol, Foie, Maladies du rein, Microsomes du foie.
- métabolisme : 11-beta-Hydroxysteroid dehydrogenase type 1, Alcohol oxidoreductases, Aldose reductase, Cytosol, Foie, Maladies du rein, Microsomes du foie, Oxidoreductases, Warfarine.
- Animaux, Modèles animaux de maladie humaine, Mâle, Rat Sprague-Dawley, Rats.
English descriptors
- KwdEn :
- 11-beta-Hydroxysteroid Dehydrogenase Type 1 (metabolism), Alcohol Oxidoreductases (metabolism), Aldehyde Reductase (metabolism), Animals, Cytosol (enzymology), Cytosol (metabolism), Disease Models, Animal, Kidney Diseases (enzymology), Kidney Diseases (metabolism), Liver (enzymology), Liver (metabolism), Male, Microsomes, Liver (enzymology), Microsomes, Liver (metabolism), Oxidoreductases (metabolism), Rats, Rats, Sprague-Dawley, Warfarin (metabolism).
- MESH :
- chemical , metabolism : 11-beta-Hydroxysteroid Dehydrogenase Type 1, Alcohol Oxidoreductases, Aldehyde Reductase, Oxidoreductases, Warfarin.
- enzymology : Cytosol, Kidney Diseases, Liver, Microsomes, Liver.
- metabolism : Cytosol, Kidney Diseases, Liver, Microsomes, Liver.
- Animals, Disease Models, Animal, Male, Rats, Rats, Sprague-Dawley.
Abstract
Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug-metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important phase I drug-metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from five-sixths-nephrectomized and control rats (n = 10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were determined using quantitative real-time polymerase chain reaction and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P < 0.001) and 43% (P < 0.01) in cytosol and microsomes, respectively, in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11β-hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P < 0.05) in CKD rats compared with controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients.
DOI: 10.1124/dmd.114.061150
PubMed: 25332430
Affiliations:
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Alshogran</name><affiliation wicri:level="4"><nlm:affiliation>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec</wicri:regionArea><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Naud, Judith" sort="Naud, Judith" uniqKey="Naud J" first="Judith" last="Naud">Judith Naud</name><affiliation wicri:level="4"><nlm:affiliation>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec</wicri:regionArea><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Ocque, Andrew J" sort="Ocque, Andrew J" uniqKey="Ocque A" first="Andrew J" last="Ocque">Andrew J. Ocque</name><affiliation wicri:level="4"><nlm:affiliation>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec</wicri:regionArea><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Leblond, Francois A" sort="Leblond, Francois A" uniqKey="Leblond F" first="François A" last="Leblond">François A. Leblond</name><affiliation wicri:level="4"><nlm:affiliation>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec</wicri:regionArea><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Pichette, Vincent" sort="Pichette, Vincent" uniqKey="Pichette V" first="Vincent" last="Pichette">Vincent Pichette</name><affiliation wicri:level="4"><nlm:affiliation>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec</wicri:regionArea><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Nolin, Thomas D" sort="Nolin, Thomas D" uniqKey="Nolin T" first="Thomas D" last="Nolin">Thomas D. Nolin</name><affiliation wicri:level="4"><nlm:affiliation>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada nolin@pitt.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec</wicri:regionArea><orgName type="university">Université de Pittsburgh</orgName><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">Drug metabolism and disposition: the biological fate of chemicals</title><idno type="eISSN">1521-009X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>11-beta-Hydroxysteroid Dehydrogenase Type 1 (metabolism)</term><term>Alcohol Oxidoreductases (metabolism)</term><term>Aldehyde Reductase (metabolism)</term><term>Animals</term><term>Cytosol (enzymology)</term><term>Cytosol (metabolism)</term><term>Disease Models, Animal</term><term>Kidney Diseases (enzymology)</term><term>Kidney Diseases (metabolism)</term><term>Liver (enzymology)</term><term>Liver (metabolism)</term><term>Male</term><term>Microsomes, Liver (enzymology)</term><term>Microsomes, Liver (metabolism)</term><term>Oxidoreductases (metabolism)</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Warfarin (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>11-beta-Hydroxysteroid dehydrogenase type 1 (métabolisme)</term><term>Alcohol oxidoreductases (métabolisme)</term><term>Aldose reductase (métabolisme)</term><term>Animaux</term><term>Cytosol (enzymologie)</term><term>Cytosol (métabolisme)</term><term>Foie (enzymologie)</term><term>Foie (métabolisme)</term><term>Maladies du rein (enzymologie)</term><term>Maladies du rein (métabolisme)</term><term>Microsomes du foie (enzymologie)</term><term>Microsomes du foie (métabolisme)</term><term>Modèles animaux de maladie humaine</term><term>Mâle</term><term>Oxidoreductases (métabolisme)</term><term>Rat Sprague-Dawley</term><term>Rats</term><term>Warfarine (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>11-beta-Hydroxysteroid Dehydrogenase Type 1</term><term>Alcohol Oxidoreductases</term><term>Aldehyde Reductase</term><term>Oxidoreductases</term><term>Warfarin</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Cytosol</term><term>Foie</term><term>Maladies du rein</term><term>Microsomes du foie</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Cytosol</term><term>Kidney Diseases</term><term>Liver</term><term>Microsomes, Liver</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cytosol</term><term>Kidney Diseases</term><term>Liver</term><term>Microsomes, Liver</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>11-beta-Hydroxysteroid dehydrogenase type 1</term><term>Alcohol oxidoreductases</term><term>Aldose reductase</term><term>Cytosol</term><term>Foie</term><term>Maladies du rein</term><term>Microsomes du foie</term><term>Oxidoreductases</term><term>Warfarine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Male</term><term>Rats</term><term>Rats, Sprague-Dawley</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Modèles animaux de maladie humaine</term><term>Mâle</term><term>Rat Sprague-Dawley</term><term>Rats</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug-metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important phase I drug-metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from five-sixths-nephrectomized and control rats (n = 10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were determined using quantitative real-time polymerase chain reaction and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P < 0.001) and 43% (P < 0.01) in cytosol and microsomes, respectively, in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11β-hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P < 0.05) in CKD rats compared with controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="Canada"><region name="Pennsylvanie"><name sortKey="Alshogran, Osama Y" sort="Alshogran, Osama Y" uniqKey="Alshogran O" first="Osama Y" last="Alshogran">Osama Y. Alshogran</name></region><name sortKey="Leblond, Francois A" sort="Leblond, Francois A" uniqKey="Leblond F" first="François A" last="Leblond">François A. Leblond</name><name sortKey="Naud, Judith" sort="Naud, Judith" uniqKey="Naud J" first="Judith" last="Naud">Judith Naud</name><name sortKey="Ocque, Andrew J" sort="Ocque, Andrew J" uniqKey="Ocque A" first="Andrew J" last="Ocque">Andrew J. Ocque</name><name sortKey="Pichette, Vincent" sort="Pichette, Vincent" uniqKey="Pichette V" first="Vincent" last="Pichette">Vincent Pichette</name></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Nolin, Thomas D" sort="Nolin, Thomas D" uniqKey="Nolin T" first="Thomas D" last="Nolin">Thomas D. Nolin</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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