Induction of cytochrome P450 1A by formula: a comparative study between human milk and formula

Abstract

Purpose Human milk reportedly contains higher levels of environmental pollutants. Many of them are potent inducers of CYP1A and exert toxic effects ranging from mutagenic effects to hormonal disruption via aryl hydrocarbon receptor (AhR) activation. Paradoxically, the elimination of caffeine, a CYP1A2 substrate used to treat neonatal apnea, is 3-fold slower in breast-fed infants than in formula-fed infants. In this study, we determined the effects of human milk and formula on AhR activity and CYP1A expression. Methods HepG2 CYP1A mRNA, protein expressions and mouse Cyp1a1 mRNA were measured. Using a luciferase reporter construct containing Cyp1a promoter, we examined HepG2 AhR activity, and determined the toxic equivalents (TEQs) of milk and formula. Results Formula but not human milk induced CYP1A mRNA and protein. Formula induced fetal mouse hepatic Cyp1a1 expression. Both cow milk-based and soy formula but not human milk showed AhR activation. The lipid fraction of formula retained the active effect on AhR. Moreover, the co-treatment of 3,4-dimethoxyflavone, an AhR antagonist, abolished formula's effect on AhR and CYP1A mRNA. Formula milk activated AhR with TEQs up to 6.4 pg TCDD/g, nearly 100-fold higher than the reported values. Conclusion Formula may increase infant drug metabolism by increasing CYP1A expression via AhR activation. Human milk does not elicit the same effect despite reported higher levels of environmental pollutants. Clinical Pharmacology & Therapeutics (2004) 75, P50–P50; doi: 10.1016/j.clpt.2003.11.190