Expression of drug-metabolizing enzymes, nuclear transcription factors and ABC transporters in Caco-2 cells.

1. Caco-2 cells are frequently used in intestinal drug absorption and metabolism studies, but little is known about the effects of drugs on the simultaneous expression of genes coding for drug-metabolizing enzymes (DMEs), nuclear transcription factors and ABC transporters. 2. The gene expression and enzyme activities of control and Aroclor 1254-treated cultures were therefore explored, the latter being a powerful inducer of DMEs. Fourteen- and 80-fold induction of CYP1A1 and CYP1A2 mRNA were shown, whereas expression of other DMEs was either increased (CYP2C8-2C19, 10-fold; CYP3A5, twofold; FMO1, 2 and 5, twofold; epoxide hydrolase, threefold) or repressed (CYP2D6 and CYP2E1 to 75% of control values). 3. Notably, gene copies of CYP3A4 and CYP2B6/7 were below the limit of detection, but a three- and 10-fold induction of HNF 1alpha + beta, HNF-4alpha4 and a similar 10-fold increase in STAT 3 and 4 was observed. 4. Similarly, c/EBP transcripts were only detected in treated cell cultures, but MRP1, its isoforms 3-5 as well as MDR-1 were increased threefold after dosing with Aroclor 1254. 5. Overall, CYP gene expression correlated well with the cognate enzyme activity using testosterone as a marker substrate.