Abstract
The ultimate fate of drugs and chemicals in the body is largely regulated by hepatic uptake, metabolism, and excretion. The liver acquires the functional ability to metabolize and transport chemicals during the perinatal period of development. Research using livers from fetal and juvenile rodents and humans has begun to reveal the timing, key enzymes and transporters, and regulatory factors that are responsible for the establishment of hepatic phase I and II metabolism as well as transport. The majority of this research has been limited to relative mRNA and protein quantification. However, the recent utilization of novel technology, such as RNA-Sequencing, and the improved availability and refinement of functional activity assays, has begun to provide more definitive information regarding the extent of hepatic drug disposition in the developing fetus. The goals of this review are to provide an overview of the early regulation of the major phase I and II enzymes and transporters in rodent and human livers and to highlight potential mechanisms that control the ontogeny of chemical metabolism and excretion pathways.
Highlights
Xenobiotics that enter the body commonly undergo metabolism by phase I and/or phase II enzymes in the liver
This review article provides a broad overview of the rodent and human studies that characterize the regulation of phase I and II enzymes and transporters during fetal liver development
While there are exceptions, such as human FMO1, which has been detected in second trimester fetal livers [5,6], the majority of phase I metabolism during early development appears to be cytochrome P450 (Cyp)-mediated biotransformation and most research in this field has focused on Cyp enzymes
Summary
Xenobiotics that enter the body commonly undergo metabolism by phase I and/or phase II enzymes in the liver. The fields of pharmacology, toxicology, and medicine have benefited greatly from advancements in understanding the developmental profiles of hepatic phase I and II drug metabolism and transport These data have aided in chemical risk assessment, exposure modeling, and age-appropriate pharmacotherapy. Around gestation day 13, hepatoblasts mature into functional rodent hepatocytes and begin the early formation of a biliary network, which continues through birth It was first observed in the 1950s that the drug metabolizing capabilities of the newborn rabbit liver are not mature at birth because of a differing enzyme profile [1]. This review article provides a broad overview of the rodent and human studies that characterize the regulation of phase I and II enzymes and transporters during fetal liver development. Attention will be placed upon regulatory pathways, including transcriptional and epigenetic factors, that contribute to the programming of biotransformation and excretion
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