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Vol. 60, Issue 6, 1260-1267, December 2001
on the
Disposition of Debrisoquine in the Mouse
Laboratory of Metabolism (J.C., C.P.G., T.E.A., G.P.H., S.P.,
F.J.G.) and Laboratory Animal Resources (L.F.), National Cancer
Institute, National Institutes of Health, Bethesda, Maryland; and
Institute for Cancer Research and Molecular Biology (J.R.I.), Norwegian
University of Science and Technology, Trondheim, Norway
CYP2D6 is a highly polymorphic human gene responsible
for a large variability in the disposition of more than 100 drugs to which humans may be exposed. Animal models are inadequate for preclinical pharmacological evaluation of CYP2D6 substrates because of
marked species differences in CYP2D isoforms. To overcome this issue, a
transgenic mouse line expressing the human CYP2D6 gene was generated. The complete wild-type CYP2D6 gene,
including its regulatory sequence, was microinjected into a fertilized
FVB/N mouse egg, and the resultant offspring were genotyped by both polymerase chain reaction and Southern blotting. CYP2D6-specific protein expression was detected in the liver, intestine, and kidney from only the CYP2D6 humanized mice. Pharmacokinetic
analysis revealed that debrisoquine (DEB) clearance was markedly higher (94.1 ± 22.3 l/h/kg), and its half-life significantly reduced (6.9 ± 1.6 h), in CYP2D6 humanized mice
compared with wild-type animals (15.2 ± 0.9 l/h/kg and 16.5 ± 4.5 h, respectively). Mutations in hepatic nuclear factor 4
(HNF4), a hepatic transcription factor known to
regulate in vitro expression of the CYP2D6 gene, could
affect the disposition of CYP2D6 drug substrates. To determine whether
the HNF4 gene modulates in vivo pharmacokinetics of
CYP2D6 substrates, a mouse line carrying both the CYP2D6
gene and the HNF4 conditional mutation was generated
and phenotyped using DEB. After deletion of HNF4, DEB
4-hydroxylase activity in CYP2D6 humanized mice
decreased more than 50%. The data presented in this study show that
only CYP2D6 humanized mice but not wild-type mice
display significant DEB 4-hydroxylase activity and that HNF4 regulates CYP2D6 activity in vivo. The CYP2D6 humanized
mice represent an attractive model for future preclinical studies on
the pharmacology, toxicology, and physiology of CYP2D6-mediated metabolism.
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