RNA Editing Enzymes Modulate the Expression of Hepatic CYP2B6, CYP2C8, and Other Cytochrome P450 Isoforms

A-to-I RNA editing, the most frequent type of RNA editing in mammals, is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. Recently, we found that there is a large interindividual variation in the expression of ADAR1 protein in the human livers. In this study, we investigated the possibility that A-to-I RNA editing may modulate the expression of cytochrome P450 (P450), causing interindividual variations in drug metabolism potencies. We found that knockdown of ADAR1 or ADAR2 in HepaRG cells resulted in the decreased expression of CYP2B6 and CYP2C8 mRNA and protein. Knockdown of ADARs significantly decreased the stability of CYP2B6 mRNA but not CYP2C8 mRNA. Luciferase assays revealed that the 39-untranslated region of CYP2B6 and the promoter region of CYP2C8 would be involved in the decrease in their expression by the knockdown of ADARs. We found that the decreased expression of the hepatocyte nuclear factor 4a (HNF4a) protein by the knockdown of ADARs was one of the reasons for the decreased transactivity of CYP2C8. The mRNA levels of other P450 isoforms, such as CYP2A6, 2C9, 2C19, 2D6, and 2E1, which are known to be regulated by HNF4a, were also decreased by ADAR1 or ADAR2 knockdown. Exceptionally, the CYP3A4 mRNA level was significantly increased by ADAR1 knockdown, suggesting the possibility that the change could be due to the change in the expression or function of other regulatory factors. In conclusion, this study revealed that the RNA editing enzymes ADAR1 and ADAR2 are novel regulatory factors of P450-mediated drug metabolism in the human liver.