Effects of human milk and formula on expression of MDR1, MRP2, and CYP3A in the C2BBE1 intestinal cell model

Abstract

Purpose The development of drug elimination mechanisms in the intestine is not well understood, posing significant challenges to pediatric therapeutics. In particular, effects of feeding on the ontogeny of drug metabolizing enzymes and transporters remain virtually unknown. Since human milk is rich in bioactive substances known for their effects on expression of enzymes and transporters, we hypothesized that human milk and formula have different activities in this regard. As a first step, we examined effects of human milk and formula on expression of CYP3A, and drug transporters, MDR1 and MRP2. Methods C2BBe1 cells, a subclone of Caco2 cells, were characterized for the protein expression time courses. They were incubated with cow milk-based formula and human milk. RT-PCR and Western blotting were used to analyze the mRNA and protein expression. Results The C2BBe1 cells showed time-dependent increase in CYP 3A4 and MRP2 expression, and decrease in CYP3A7 and MDR1. Using the time window with expression-stable culture, we observed that 72-hr exposure to 10-20% human milk induced MRP2 mRNA/protein by more than 2–fold, and MDR1 protein without apparent change at the mRNA level. Human milk had the tendency to inhibit CYP3A4 expression but there was no statistical change. Formula had no effect. Conclusion Compared to formula, human milk causes transcriptional induction of MRP2, and post-transcriptional induction of MDR1 in the intestinal cell model. Clinical Pharmacology & Therapeutics (2004) 75, P51–P51; doi: 10.1016/j.clpt.2003.11.191