Extending Investigations of miR-126-5p on the Regulation of CYP2A6, the Major Nicotine-Inactivating Enzyme

Abstract

CYP2A6 is the hepatic enzyme responsible for the metabolic inactivation of nicotine. Variation in CYP2A6 alters nicotine clearance, affecting numerous smoking behaviors and tobacco-related diseases, making investigating sources of variation important. A published molecular study of microRNA-126-5p, the microRNA-126 functional arm, showed it decreased CYP2A6 expression post-transcriptionally; it also showed that higher CYP2A7 mRNA competed for microRNA-126-5p binding, mitigating the CYP2A6 reduction. To extend these observations, we investigated relationships between microRNA-126-5p and CYP2A6 protein and activity using a large human liver bank (n = 282). MicroRNA-126-5p was not inversely correlated with CYP2A6 protein (r_s = 0.04, p > 0.05), nor was it significant in an unadjusted regression model (p > 0.05) or in an adjusted model (with genotype, age, and sex) (p > 0.05). Although CYP2A7 mRNA was positively correlated with CYP2A6 protein (r_s = 0.48, p < 0.001), adding CYP2A7 mRNA to the adjusted model did not alter the relationship between microRNA-126-5p and CYP2A6 protein (p > 0.05), nor did CYP2A7 mRNA interact with microRNA-126-5p on CYP2A6 (p > 0.05). Similar results were found in modeling CYP2A6 activity. MicroRNA-21 was used as a positive control (inversely correlated with CYP2A6 protein, r_s = -0.33, p < 0.001) and microRNA-152 as a negative control (not correlated with CYP2A6 protein, r_s = -0.06, p > 0.05). These data do not support a role for microRNA-126-5p in downregulating CYP2A6 protein or activity, or for CYP2A7 mRNA in playing a decoy role, even when other predictors (genotype, age, and sex) were included in the model.