Deregulation of the Genes that Are Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Hepatocellular Carcinoma.

ABSTRACT

Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are called ADME genes. Currently, 298 genes that encode phase I and II drug metabolizing enzymes, transporters, and modifiers are designated as ADME genes by the PharmaADME Consortium. ADME genes are highly expressed in the liver and their levels can be influenced by liver diseases such as hepatocellular carcinoma (HCC). In this study, we obtained RNA-sequencing and microRNA (miRNA)-sequencing data from 371 HCC patients via The Cancer Genome Atlas liver hepatocellular carcinoma project and performed ADME gene-targeted differential gene expression analysis and expression correlation analysis. Two hundred thirty-three of the 298 ADME genes (78%) were expressed in HCC. Of these genes, almost one-quarter (58 genes) were significantly downregulated, while only 6% (15) were upregulated in HCC relative to healthy liver. Moreover, one-half (14/28) of the core ADME genes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4, NAT1, NAT2, UGT2B7, SLC22A1, SLCO1B1, and SLCO1B3) were downregulated. In addition, about one-half of the core ADME genes were positively correlated with each other and were also positively (AHR, ARNT, HNF4A, PXR, CAR, PPARA, and RXRA) or negatively (PPARD and PPARG) correlated with transcription factors known as ADME modifiers. Finally, we show that most miRNAs known to regulate core ADME genes are upregulated in HCC. Collectively, these data reveal 1) an extensive transcription factor-mediated ADME coexpression network in the liver that efficiently coordinates the metabolism and elimination of endogenous and exogenous compounds; and 2) a widespread deregulation of this network in HCC, most likely due to deregulation of both transcriptional and post-transcriptional (miRNA) pathways.