Expression and distribution of CYP3A genes, CYP2B22, and MDR1, MRP1, MRP2, LRP efflux transporters in brain of control and rifampicin-treated pigs

The in vivo effect of rifampicin, a potent ligandof PXR, on gene expression of CYP2B22, 3A22, 3A29, 3A46, CAR, PXR and MDR1, MRP1, MRP2, LRP trans-porters in liver and cortex, cerebellum, midbrain, hippo-campus, meninges and brain capillaries of pig wasinvestigated. Animals were treated i.p. with four daily dosesof rifampicin (40 mg/kg). The basal mRNA expressions ofthe individual CYP3As, CYP2B22, CAR, and PXR in var-ious brain regions, except meninges, were about or below10% of the corresponding hepatic mRNA values, whereasthe mRNAs of brain transporters were closer or comparableto those in liver. After pig treatment with rifampicin, themRNA expression of CYPs and transporters from brainregions did not appear to change, except CYP3A22 and3A29 in cortex and hippocampus, CYP2B22 in meninges. An enzymatic analysis for CYP3As and CYP2B, in micro-somes and mitochondria from liver and brain tissues usingthe marker activities 7-benzyloxyquinoline O-debenzylaseand the anthraldehyde oxidase, showed the lack of rifam-picin induction in all the brain regions, unlike liver. Taken together, our results demonstrate that CYP2B22, CYP3As,and MDR1, MRP1, MRP2, and LRP transporters are allexpressed, although at different extent, in the brain regionsbut, despite the presence of PXR and CAR, are resistant toinduction indicating that the regulation of these proteins ismore complex in brain than in liver. These data obtained invivo in the brain regions and liver of pig may be of interest tohuman metabolism in CNS.