Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdr1 genes

We hypothesized that the drug efflux protein P-glycoprotein (Pgp), the prod uct of the multidrug resistance gene MDR1, might influence hepatic expressi on of CYP3A or other cytochromes P-450 (P-450s) because Pgp can transport e ndogenous regulators of these cytochromes. We began with variants of a CF-1 mouse strain containing a defective mdr1a gene that is inherited in a Mend elian fashion. The amount of CYP3A protein in liver was inversely related t o the gene dose of the normal mdr1a allele in these mice. mdr1a knockout mi ce of either mixed (FVB x 129/Ola) or pure FVB genetic background and house d 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 md r1b might mask the overall effect of mdr1a absence on P-450 gene expression . Targeted inactivation of the mdr1b gene increased P-450 expression, but t he effect was modest compared with mdr1a ablation. Mice nullizygous for bot h mdr1a and mdr1b-type Pgps and kept in Amsterdam had dramatically increase d levels of CYP3A protein as well as other P-450s examined and of the elect ron donor P-450 reductase. Consistent with the protein results, CYP3A catal ytic activity measured as midazolam 1'- and 4-hydroxylation in liver micros omes from these knockout mice revealed a rank order of activities with mdr1 a/1b > mdr1a > mdr1b > (1/1) 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 mdr 1 genotype or actually showed a slight decrease in mdr1a (-/-) mice. These results provide a revealing picture of mdr1-type Pgp as an upstream regulat or of hepatic P-450 expression, and demonstrate that these pharmacologicall y relevant phenotypes in knockout mice depend not only on the genetic make- up of the mice but also on the environment.