Drug Metab Dispos. 2026 Apr 30;54(6):100314. doi: 10.1016/j.dmd.2026.100314. Online ahead of print.
ABSTRACT
Drug safety assessment in newborns is limited by ethical constraints and the fact that no appropriate human-relevant in vitro hepatic cell model system currently exists to study and predict drug metabolism and disposition in this fragile population. Yet polypharmacy and off-label drug administration to newborns in the neonatal intensive care unit substantially increases the risk for drug adverse events in a population characterized by an immature hepatic drug metabolizing enzyme (DME) system. To address this concern, we differentiated induced pluripotent stem cells from adult donors into human hepatocyte-like cells (hHLC3A7) exhibiting metabolic activity of the unique fetal/newborn CYP3A7. Compared with newborn and functionally mature primary human hepatocytes (PHHs), the hHLC3A7 model displayed a mix of fetal hepatic markers and neonatal DME genes, and was quite distinct from mature PHHs with high DME expression. Notably, hHLC3A7 demonstrated the ability to metabolize the endogenous steroid hormone dehydroepiandrosterone to its 16α-hydroxy derivative, the major metabolite produced by CYP3A7 and an important precursor in estriol biosynthesis. In addition, hHLC3A7 metabolized the drug midazolam at equal rate for 1′- and 4-hydroxylation, as observed in newborn PHH. The hHLC3A7 model’s utility was further probed for applications in xenobiotic CYP3A induction and CYP3A bioactivation of the fungal toxin, aflatoxin B1. Although further research is needed to understand the molecular mechanisms regulating CYP3A ontogeny to achieve maximal enzymatic activity, our hHLC3A7 model establishes a sustainable and valuable platform for investigating CYP3A7-mediated xenobiotic metabolism and potential drug-drug or drug-hormone interaction risk during an intricate developmental stage influenced by fluctuating gestational age. SIGNIFICANT STATEMENT: The lack of in vitro models for studying newborn xenobiotic metabolism increases the vulnerability of this population to adverse drug reactions. This work demonstrates human-derived induced pluripotent stem cells can be differentiated into a CYP3A7-centric hepatocyte-like cellular model that recapitulates important drug metabolizing gene expression and metabolic functions when compared with newborn hepatocytes.
PMID:42224858 | DOI:10.1016/j.dmd.2026.100314