LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver
Metabolic transformation by the superfamily of cytochromes P450 (CYPs) plays an important role in the detoxification of xenobiotics such as drugs, environmental pollutants, and food additives. Endogenous substrates of CYPs include fatty acids, sterols, steroids, and bile acids. Induction of CYPs via...
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| Format: | Article |
| Language: | English |
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Elsevier
2005-08-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752032962X |
| _version_ | 1818931360172081152 |
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| author | Carmela Gnerre Gertrud U. Schuster Adrian Roth Christoph Handschin Lisen Johansson Renate Looser Paolo Parini Michael Podvinec Kirsten Robertsson Jan-Åke Gustafsson Urs A. Meyer |
| author_facet | Carmela Gnerre Gertrud U. Schuster Adrian Roth Christoph Handschin Lisen Johansson Renate Looser Paolo Parini Michael Podvinec Kirsten Robertsson Jan-Åke Gustafsson Urs A. Meyer |
| author_sort | Carmela Gnerre |
| collection | DOAJ |
| description | Metabolic transformation by the superfamily of cytochromes P450 (CYPs) plays an important role in the detoxification of xenobiotics such as drugs, environmental pollutants, and food additives. Endogenous substrates of CYPs include fatty acids, sterols, steroids, and bile acids. Induction of CYPs via transcriptional activation by substrates and other xenobiotics is an important adaptive mechanism that increases the organism's defense capability against toxicity. Numerous in vivo and in vitro data have highlighted the concept that the molecular mechanism of hepatic drug induction is linked to endogenous regulatory pathways. In particular, in vitro data suggest that oxysterols via the liver X receptor (LXR) inhibit phenobarbital (PB)-mediated induction of CYPs. To study the link between LXR, cholesterol homeostasis, and drug induction in vivo, we designed experiments in wild-type, LXRα-, LXRβ-, and LXRα/β-deficient mice. Our data expose differential regulatory patterns for Cyp2b10 and Cyp3a11 dependent on the expression of LXR isoforms and on challenge of cholesterol homeostasis by excess dietary cholesterol.Our results suggest that, in the mouse, liver cholesterol status significantly alters the pattern of expression of Cyp3a11, whereas the absence of LXR leads to an increase in PB-mediated activation of Cyp2b10. |
| first_indexed | 2024-12-20T04:15:21Z |
| format | Article |
| id | doaj.art-19b6177f923d42119c5da31c61435675 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-20T04:15:21Z |
| publishDate | 2005-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-19b6177f923d42119c5da31c614356752022-12-21T19:53:48ZengElsevierJournal of Lipid Research0022-22752005-08-0146816331642LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liverCarmela Gnerre0Gertrud U. Schuster1Adrian Roth2Christoph Handschin3Lisen Johansson4Renate Looser5Paolo Parini6Michael Podvinec7Kirsten Robertsson8Jan-Åke Gustafsson9Urs A. Meyer10Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, SwitzerlandDepartment of Biosciences at Novum, Karolinska Institutet, S-141 57 Huddinge, SwedenDivision of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, SwitzerlandDepartment of Cancer Biology, Dana-Farber Cancer Institute, and Department of Cell Biology, Harvard Medical School, Boston, MA 02115Department of Biosciences at Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden; Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Novum, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, SwedenDivision of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, SwitzerlandDepartment of Biosciences at Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden; Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Novum, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, SwedenDivision of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, SwitzerlandDepartment of Biosciences at Novum, Karolinska Institutet, S-141 57 Huddinge, SwedenDepartment of Biosciences at Novum, Karolinska Institutet, S-141 57 Huddinge, SwedenTo whom correspondence should be addressed.; Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, SwitzerlandMetabolic transformation by the superfamily of cytochromes P450 (CYPs) plays an important role in the detoxification of xenobiotics such as drugs, environmental pollutants, and food additives. Endogenous substrates of CYPs include fatty acids, sterols, steroids, and bile acids. Induction of CYPs via transcriptional activation by substrates and other xenobiotics is an important adaptive mechanism that increases the organism's defense capability against toxicity. Numerous in vivo and in vitro data have highlighted the concept that the molecular mechanism of hepatic drug induction is linked to endogenous regulatory pathways. In particular, in vitro data suggest that oxysterols via the liver X receptor (LXR) inhibit phenobarbital (PB)-mediated induction of CYPs. To study the link between LXR, cholesterol homeostasis, and drug induction in vivo, we designed experiments in wild-type, LXRα-, LXRβ-, and LXRα/β-deficient mice. Our data expose differential regulatory patterns for Cyp2b10 and Cyp3a11 dependent on the expression of LXR isoforms and on challenge of cholesterol homeostasis by excess dietary cholesterol.Our results suggest that, in the mouse, liver cholesterol status significantly alters the pattern of expression of Cyp3a11, whereas the absence of LXR leads to an increase in PB-mediated activation of Cyp2b10.http://www.sciencedirect.com/science/article/pii/S002222752032962Xliver X receptorpregnane X receptorconstitutive androstane receptormetabolismcytochrome P450 3a11cytochrome P450 2b10 |
| spellingShingle | Carmela Gnerre Gertrud U. Schuster Adrian Roth Christoph Handschin Lisen Johansson Renate Looser Paolo Parini Michael Podvinec Kirsten Robertsson Jan-Åke Gustafsson Urs A. Meyer LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver Journal of Lipid Research liver X receptor pregnane X receptor constitutive androstane receptor metabolism cytochrome P450 3a11 cytochrome P450 2b10 |
| title | LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver |
| title_full | LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver |
| title_fullStr | LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver |
| title_full_unstemmed | LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver |
| title_short | LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver |
| title_sort | lxr deficiency and cholesterol feeding affect the expression and phenobarbital mediated induction of cytochromes p450 in mouse liver |
| topic | liver X receptor pregnane X receptor constitutive androstane receptor metabolism cytochrome P450 3a11 cytochrome P450 2b10 |
| url | http://www.sciencedirect.com/science/article/pii/S002222752032962X |
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