Stereoselective regulation of MDR1 expression in Caco‐2 cells by cetirizine enantiomers

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Abstract
MDR1‐encoded P‐glycoprotein (P‐gp) is a drug efflux transporter mainly expressed in liver, kidney, intestine, brain (at the level of the blood‐brain barrier), and placenta. It thus plays important roles in drug absorption, distribution, and excretion. Cetirizine is a second‐generation nonsedating antihistamine used to treat allergic disease of respiratory system, skin and eyes. To evaluate P‐gp expression and function in Caco‐2 cells pretreated with cetirizine enantiomers, we assessed the sensitivity of Caco‐2 cells to paclitaxel using the MTT assay and the polarized transport of rhodamine‐123 and doxorubicin across Caco‐2 monolayers. RT‐PCR and flow cytometry were used to assay MDR1 mRNA and P‐gp protein respectively. The sensitivity of Caco‐2 cells to paclitaxel decreased significantly after cells were pretreated with 100 μM R‐cetirizine but increased upon treatment with S‐cetirizine. The efflux of rhodamine‐123 and doxorubicin was enhanced significantly after Caco‐2 monolayers were pretreated with 100 μM R‐cetirizine but was reduced by S‐cetirizine. The MDR1 mRNA and P‐gp levels in Caco‐2 cells were increased by 100 μM R‐cetirizine and decreased by 100 μM S‐cetirizine. These results suggest that R‐cetirizine up‐regulates MDR1 expression while S‐cetirizine down‐regulates MDR1 expression. Chirality, 2007.

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