Effects of infant formula, cow milk and human milk on drug metabolizing enzymes

Abstract

Background Caffeine, used for treating neonatal apnea, is eliminated 3-fold slower in breastfed infants than in formula-fed infants. Caffeine is metabolized by cytochrome P450 (CYP) 1A and CYP3A4, which are regulated by aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) respectively. Here we hypothesized that formula but not human milk induces CYP1A and/or CYP3A4 via their regulatory pathways. Methods Human milk samples from healthy lactating women were collected. Infant formula and cow milk were purchased. Lipid fraction of milk samples was obtained by organic extraction. mRNA and protein expression were measured by RT-PCR and western blotting. Reporter plasmids containing receptor response elements were tested for their activation. Results CYP1A expression and AhR activity were induced by formula and cow milk but not by human milk. The AhR activation by formula was abolished by co-treatment of Ah antagonist. Formula and human milk also had differential effects on AhR activation by dibenz[a,h]anthracene, an AhR agonist. In addition, lipid fraction of formula but not human milk activated AhR. Both formula and human milk showed mild induction of CYP3A4 mRNA and PXR. However, co-transfection of hPXR did not increase PXR activation by milk treatments, suggesting a non PXR-mediated pathway. Conclusion Infant formula but not human milk contains AhR agonist(s) that induces CYP1A expression. Both infant formula and human milk induce CYP3A4 through non PXR-mediated pathway. Clinical Pharmacology & Therapeutics (2005) 77, P46–P46; doi: 10.1016/j.clpt.2004.12.068