Discovery - University of Dundee - Online Publications

Library & Learning Centre

Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism

Standard

Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism. / McLaughlin, Lesley A.; Ronseaux, Sebastien; Finn, Robert D.; Henderson, Colin J.; Wolf, C. Roland (Lead / Corresponding author).

In: Molecular Pharmacology, Vol. 78, No. 2, 08.2010, p. 269-278.

Research output: Contribution to journalArticle

Harvard

McLaughlin, LA, Ronseaux, S, Finn, RD, Henderson, CJ & Wolf, CR 2010, 'Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism' Molecular Pharmacology, vol 78, no. 2, pp. 269-278., 10.1124/mol.110.064246

APA

McLaughlin, L. A., Ronseaux, S., Finn, R. D., Henderson, C. J., & Wolf, C. R. (2010). Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism. Molecular Pharmacology, 78(2), 269-278. 10.1124/mol.110.064246

Vancouver

McLaughlin LA, Ronseaux S, Finn RD, Henderson CJ, Wolf CR. Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism. Molecular Pharmacology. 2010 Aug;78(2):269-278. Available from: 10.1124/mol.110.064246

Author

McLaughlin, Lesley A.; Ronseaux, Sebastien; Finn, Robert D.; Henderson, Colin J.; Wolf, C. Roland (Lead / Corresponding author) / Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism.

In: Molecular Pharmacology, Vol. 78, No. 2, 08.2010, p. 269-278.

Research output: Contribution to journalArticle

Bibtex - Download

@article{baf4654009d74c18884978e408369ed0,
title = "Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism",
keywords = "NADPH-CYTOCHROME-P450 REDUCTASE, ELECTRON-TRANSFER, 17,20-LYASE ACTIVITY, ESCHERICHIA-COLI, P450 REDUCTASE, BINDING-SITE, LIVER, EXPRESSION, ROLES, RAT",
author = "McLaughlin, {Lesley A.} and Sebastien Ronseaux and Finn, {Robert D.} and Henderson, {Colin J.} and Wolf, {C. Roland}",
year = "2010",
doi = "10.1124/mol.110.064246",
volume = "78",
number = "2",
pages = "269--278",
journal = "Molecular Pharmacology",
issn = "0026-895X",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Deletion of Microsomal Cytochrome b(5) Profoundly Affects Hepatic and Extrahepatic Drug Metabolism

A1 - McLaughlin,Lesley A.

A1 - Ronseaux,Sebastien

A1 - Finn,Robert D.

A1 - Henderson,Colin J.

A1 - Wolf,C. Roland

AU - McLaughlin,Lesley A.

AU - Ronseaux,Sebastien

AU - Finn,Robert D.

AU - Henderson,Colin J.

AU - Wolf,C. Roland

PY - 2010/8

Y1 - 2010/8

N2 - <p>We demonstrated recently that cytochrome b(5) plays an important in vivo role in hepatic cytochrome P450 (P450) function [J Biol Chem 283: 31385-31393, 2008]. We have now generated a model in which cytochrome b 5 has been deleted in all tissues [cytochrome b(5) complete null (BCN)], which surprisingly results in a viable mouse despite the putative in vivo roles of this protein in lipid and steroid hormone metabolism and the reduction of methemoglobin. In contrast to the liver-specific deletion, complete deletion of cytochrome b(5) leads to a neonatal increase in the expression of many hepatic P450s at both the protein and mRNA level. In extrahepatic tissues, some changes in P450 expression were also observed that were isoform-dependent. In vitro cytochrome P450 activities in liver, kidney, lung, and small intestine of BCN mice were determined for a range of model substrates and probe drugs; a profound reduction in the metabolism of some substrates, particularly in lung, kidney, and small intestine, was observed. In vivo, the metabolism of metoprolol was significantly altered in BCN mice, in contrast to the previous finding in the liver-specific cytochrome b(5) deletion, suggesting that extrahepatic cytochrome b(5) plays a significant role in its disposition. Testicular Cyp17 hydroxylase and lyase activities were also significantly reduced by cytochrome b(5) deletion, leading to significantly lower levels of testicular testosterone. The BCN mouse provides an additional model system with which to further investigate the functions of cytochrome b(5), particularly in extrahepatic tissues.</p>

AB - <p>We demonstrated recently that cytochrome b(5) plays an important in vivo role in hepatic cytochrome P450 (P450) function [J Biol Chem 283: 31385-31393, 2008]. We have now generated a model in which cytochrome b 5 has been deleted in all tissues [cytochrome b(5) complete null (BCN)], which surprisingly results in a viable mouse despite the putative in vivo roles of this protein in lipid and steroid hormone metabolism and the reduction of methemoglobin. In contrast to the liver-specific deletion, complete deletion of cytochrome b(5) leads to a neonatal increase in the expression of many hepatic P450s at both the protein and mRNA level. In extrahepatic tissues, some changes in P450 expression were also observed that were isoform-dependent. In vitro cytochrome P450 activities in liver, kidney, lung, and small intestine of BCN mice were determined for a range of model substrates and probe drugs; a profound reduction in the metabolism of some substrates, particularly in lung, kidney, and small intestine, was observed. In vivo, the metabolism of metoprolol was significantly altered in BCN mice, in contrast to the previous finding in the liver-specific cytochrome b(5) deletion, suggesting that extrahepatic cytochrome b(5) plays a significant role in its disposition. Testicular Cyp17 hydroxylase and lyase activities were also significantly reduced by cytochrome b(5) deletion, leading to significantly lower levels of testicular testosterone. The BCN mouse provides an additional model system with which to further investigate the functions of cytochrome b(5), particularly in extrahepatic tissues.</p>

KW - NADPH-CYTOCHROME-P450 REDUCTASE

KW - ELECTRON-TRANSFER

KW - 17,20-LYASE ACTIVITY

KW - ESCHERICHIA-COLI

KW - P450 REDUCTASE

KW - BINDING-SITE

KW - LIVER

KW - EXPRESSION

KW - ROLES

KW - RAT

UR - http://www.scopus.com/inward/record.url?scp=77954890052&partnerID=8YFLogxK

U2 - 10.1124/mol.110.064246

DO - 10.1124/mol.110.064246

M1 - Article

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

VL - 78

SP - 269

EP - 278

ER -

Documents

Library & Learning Centre

Contact | Accessibility | Policy