Journal of Drug Metabolism & Toxicology
Open Access

Abstract

Higher Expressions of Cytochrome P450, UDP-Glucuronosyltransferase, and Transporter Genes in Nanopillar-Cultured Rat Hepatocyte Spheroids

Ryosuke Takahashi, Akiko Hisada and Hiroshi Sonoda

Primary hepatocytes have been widely explored as cell sources for the study of in vitro drug metabolism and pharmacokinetics (DMPK). Aiming toward establishing an in vitro drug screening method, the objective of the current study is to illustrate a comprehensive increase in the DMPK-related gene expression of nanopillar (NP)-cultured 3D-spheroids. To examine the expressional changes in DMPK-related genes under four different conditions, namely, NP-, sandwich (SW)-, monolayer (ML)-cultured rat hepatocytes, and freshly isolated hepatocytes, genome-wide gene-expression analysis using a DNA microarray was performed. Among the DMPK-related genes, cytochrome P450, UDP-glucuronosyltransferase, and transporter genes were focused on. Principal component analysis showed that the global gene expression profile in a sample from an NP culture was closer to that from freshly isolated hepatocytes than to that from an SW culture. The expressions of almost all Cyp 1 to 3 and Ugt genes of NP-cultured 3-D spheroids were higher than those of ML and SW. The expression of the Abcc2 gene, whose translation product has a critical role in the excretion of metabolized bile acids in hepatocyte to bile canaliculi, was three times higher in NP than in ML. From these results, 3-D spheroids formed by the NP culture were suggested to possess a higher ability of metabolism and excretion than does 2-D tissue formed by the conventional monolayer culture.