Effect of hepatitis C virus infection on the mRNA expression of drug transporters and cytochrome p450 enzymes in chimeric mice with humanized liver.
The expression of drug transporters and metabolizing enzymes is a primary determinant of drug disposition. Chimeric mice with humanized liver, including PXB mice, are an available model that is permissive to the in vivo infection of hepatitis C virus (HCV), thus being a promising tool for investigational studies in development of new antiviral molecules. To investigate the potential of HCV infection to alter the pharmacokinetics of small molecule antiviral therapeutic agents in PXB mice, we have comprehensively determined the mRNA expression profiles of human ATP-binding cassette (ABC) transporters, solute carrier (SLC) transporters, and cytochrome P450 (P450) enzymes in the livers of these mice under noninfected and HCV-infected conditions. Infection of PXB mice with HCV resulted in an increase in the mRNA expression levels of a series of interferon-stimulated genes in the liver. For the majority of genes involved in drug disposition, minor differences in the mRNA expression of ABC and SLC transporters as well as P450s between the noninfected and HCV-infected groups were observed. The exceptions were statistically significantly higher expression of multidrug resistance-associated protein 4 and organic anion-transporting polypeptide 2B1 and lower expression of organic cation transporter 1 and CYP2D6 in HCV-infected mice. Furthermore, the enzymatic activities of the major human P450s were, in general, comparable in the two experimental groups. These data suggest that the pharmacokinetic properties of small molecule antiviral therapies in HCV-infected PXB mice are likely to be similar to those in noninfected PXB mice. However, caution is needed in the translation of this relationship to HCV-infected patients as the PXB mouse model does not accurately reflect the pathology of patients with chronic HCV infection.
Kikuchi
Ryota
R
Non Clinical Safety, Department of Drug Metabolism and Pharmacokinetics, Viral Disease Biology, and Molecular Medicine Laboratories (P.O.), Roche Palo Alto, Palo Alto, California, USA.
McCown
Matthew
M
Olson
Pamela
P
Tateno
Chise
C
Morikawa
Yoshio
Y
Katoh
Yumiko
Y
Bourdet
David L
DL
Monshouwer
Mario
M
Fretland
Adrian J
AJ
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006526:Hepatitis C / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000821:virology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis*; D012709:Serum Albumin / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D018183:Transplantation Chimera / Q000235:genetics / Q000378:metabolism* / Q000821:virology
D002352:Carrier Proteins; D012333:RNA, Messenger; D012709:Serum Albumin; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System