Effect of claudin on cytochrome P450 activity

Abstract

Epithelial cells (ECs) cover the surfaces of the body and form the first‐line of defense against xenobiotics. The defense barrier comprises the intercellular seals, known as tight junctions (TJs), between adjacent epithelial cells and the intracellular defense systems, including cytochrome P450s (CYPs) and transporters. However, cross‐talk between the intercellular and the intracellular defense systems has not been investigated. Here, we investigated the effects of a TJs‐seal component, claudin (CL), on CYPs in Huh7 cells. A Huh7 sub‐cell line (S7d6) was screened for resistance to hepatitis C virus infection, which involves the CL‐1 co‐receptor. Western blot and quantitative PCR (qPCR) analyses revealed that CL‐1 was deficient in S7d6 cells. CYP3A4 activity was higher in S7d6 cells than in Huh7 cells and qPCR analysis confirmed that CYP3A4 mRNA was higher in S7d6 cells than in Huh7 cells. To evaluate functional CYP3A4 activity, we investigated the cytotoxicity of cyclophosphamide (CPA) in S7d6 cells because CPA is a substrate of CYP3A4 and is toxified by CYP3A4. S7d6 cells were more sensitive than Huh7 cells to CPA. These results suggest that CL‐seals might be associated with the activity of CYPs in the epithelial defense system. This work was supported by grants from MEXT (24390042) and from the Ministry of Health, Labor, and Welfare of Japan.