Xenobiotic-metabolizing enzyme and transporter gene expression in primary cultures of human hepatocytes modulated by ToxCast chemicals.

Primary human hepatocyte cultures are useful in vitro model systems of human liver because when cultured under appropriate conditions the hepatocytes retain liver-like functionality such as metabolism, transport, and cell signaling. This model system was used to characterize the concentration- and time-response of the 320 ToxCast chemicals for changes in expression of genes regulated by nuclear receptors. Fourteen gene targets were monitored in quantitative nuclease protection assays: six representative cytochromes P-450, four hepatic transporters, three Phase II conjugating enzymes, and one endogenous metabolism gene involved in cholesterol synthesis. These gene targets are sentinels of five major signaling pathways: AhR, CAR, PXR, FXR, and PPARα. Besides gene expression, the relative potency and efficacy for these chemicals to modulate cellular health and enzymatic activity were assessed. Results demonstrated that the culture system was an effective model of chemical-induced responses by prototypical in...