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Vol. 57, Issue 1, 188-197, January 2000
Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, Memphis, Tennessee (E.G.S, K.Y., C.B., L.N., M.V.R.,
J.D.S.); Department of Safety Assessment Merck Research Laboratories,
West Point, Pennsylvania (D.R.U.); and Division of Molecular Biology,
the Netherlands Cancer Institute, Amsterdam, the Netherlands (A.H.S.)
We hypothesized that the drug efflux protein P-glycoprotein (Pgp), the
product of the multidrug resistance gene MDR1, might influence hepatic expression of CYP3A or other cytochromes P-450 (P-450s) because Pgp can transport endogenous regulators of these cytochromes. We began with variants of a CF-1 mouse strain containing a
defective mdr1a gene that is inherited in a Mendelian
fashion. The amount of CYP3A protein in liver was inversely related to the gene dose of the normal mdr1a allele in these mice.
mdr1a knockout mice of either mixed (FVB × 129/Ola) or pure FVB genetic background and housed in Amsterdam display
an increased expression of CYP2B and CYP3A proteins. However, because
mdr1a ablation causes a compensatory increase in hepatic
mdr1b (which can efflux intracellular glucocorticoids),
we reasoned that mdr1b might mask the overall effect of
mdr1a absence on P-450 gene expression. Targeted
inactivation of the mdr1b gene increased P-450
expression, but the effect was modest compared with
mdr1a ablation. Mice nullizygous for both mdr1a and mdr1b-type Pgps and kept in
Amsterdam had dramatically increased levels of CYP3A protein as well as
other P-450s examined and of the electron donor P-450 reductase.
Consistent with the protein results, CYP3A catalytic activity measured
as midazolam 1'- and 4-hydroxylation in liver microsomes from these
knockout mice revealed a rank order of activities with
mdr1a/1b > mdr1a > mdr1b > (+/+) mice. In contrast to results in mice
housed in Amsterdam, in the genetically identical mdr1a
or mdr1a/1b (
/) male mice housed in the United
States, hepatic P-450 expression was unaffected by mdr1
genotype or actually showed a slight decrease in mdr1a
(/) mice. These results provide a revealing picture of
mdr1-type Pgp as an upstream regulator of hepatic P-450
expression, and demonstrate that these pharmacologically relevant
phenotypes in knockout mice depend not only on the genetic make-up of
the mice but also on the environment.
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