TY  - JOUR
A1  - Scheer, Nico
A1  - Mclaughlin, Lesley A.
A1  - Rode, Anja
A1  - MacLeod, Alastair Kenneth
A1  - Henderson, Colin J.
A1  - Wolf, Roland C.
T1  - Deletion of thirty murine cytochrome P450 genes results in viable mice with compromised drug metabolism
JF  - Drug Metabolism and Disposition
N2  - In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.
Y1  - 2014
U6  - http://dx.doi.org/10.1124/dmd.114.057885
SN  - 1521-009X
VL  - 42
IS  - 6
SP  - 1022
EP  - 1030
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Oswald, Stefan
A1  - Busch, Diana
A1  - Mclaughlin, Lesley A.
A1  - Lin, De
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
T1  - Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model
JF  - Drug Metabolism and Disposition
Y1  - 2015
U6  - http://dx.doi.org/10.1124/dmd.115.065656
SN  - 1521-009x
VL  - 43
IS  - 11
SP  - 1679
EP  - 1690
PB  - ASPET
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Henderson, Colin J.
A1  - Mclaughlin, Lesley A.
A1  - Scheer, Nico
A1  - Stanley, Lesley A.
A1  - Wolf, C. Roland
T1  - Cytochrome b5 Is a Major Determinant of Human Cytochrome P450 CYP2D6 and CYP3A4 Activity In Vivo s
JF  - Molecular Pharmacology
Y1  - 2015
U6  - http://dx.doi.org/10.1124/mol.114.097394
SN  - 1521-0111
VL  - 87
IS  - 4
SP  - 733
EP  - 739
PB  - ASPET
CY  - Bethesda
ER  -