Expression of Hepatic Drug-Metabolizing Cytochrome P450 & Uridine 5ꞌ-Glucuronosyltransferase Enzymes and their Inter-Correlations: Meta-Analysis & Experimental Study

Cytochrome P450 (CYP) and uridine 5ꞌ-glucuronosyltransferase (UGT) enzymes catalyze reactions involved in the metabolism of drugs and other xenobiotics. These enzymes are, therefore, important in pharmacological and toxicological studies and information on their abundances and correlations of expression is of value in the process of scaling in vitro data to in vivo metabolic parameters. Meta-analysis was applied to data on abundance of human hepatic cytochrome P450 and UGT enzymes in Caucasian adult livers (49 studies on CYPs and 7 studies on UGTs)[1,2] in addition to in-house data on CYP and UGT abundances in human livers[3]. In spite of variation in methodologies used to measure the abundances of CYP and UGT enzymes, agreement between the studies in 26 different laboratories in the case of CYPs and 5 different centers in the case of UGTs was generally good. More importantly, large inter-individual variability was observed in the collated data. Significant positive correlations between the expression levels of CYP and UGT enzymes were found based on the abundance data including the pairs: CYP3A4/3A5*1/*3 (Rs = 0.70, p <0.0001, n = 52), CYP3A4/2C8 (Rs = 0.68, p <0.0001, n = 134), CYP3A4/2C9 (Rs = 0.55, p <0.0001, n = 71), CYP2C8/CYP2C9 (Rs = 0.55, p <0.0001, n = 99), UGT1A4/2B4 (Rs = 0.71, p <0.0001, n = 82), UGT2B4/2B15 (Rs = 0.63, p <0.0001, n = 83), and UGT2B7/2B15 (Rs = 0.81, p <0.0001, n = 99). These correlations were confirmed using our in-house assay[3]. The correlations of expression can be used to demonstrate common genetic transcriptional mechanisms.[1]Achour et al., 2014, DMD, 42(8), 1349-1356[2]Achour et al., 2014, BDD, 35(6), 353-361[3]Achour et al., 2014, DMD, 42(4), 500-510