The Ontogeny of Human Drug-Metabolizing Enzymes: Phase I Oxidative Enzymes: Table 1

Abstract

Although some patterns are beginning to emerge, our knowledge of human phase I drug-metabolizing enzyme developmental expression remains far from complete. Expression has been observed as early as organogenesis, but this appears restricted to a few enzymes. At least two of the enzyme families that are expressed in the fetal liver exhibit a temporal switch in the immediate perinatal period (e.g., CYP3A7 to CYP3A4/3A5 and FMO1 to FMO3), whereas others show a progressive change in isoform expression through gestation (e.g., the class I alcohol dehydrogenases). Many of the phase I drug-metabolizing enzyme exhibit dynamic perinatal expression changes that are regulated primarily by mechanisms linked to birth and secondarily to maturity. A few of these enzymes are not detectable until well after birth, suggesting that birth is necessary but not sufficient for the onset of expression (e.g., CYP1A2). Tissue-specific expression adds to the complexity during ontogeny. For example, CYP3A7 expression is restricted to the fetal liver. However, with few exceptions, complete temporal relationship information during development is not known. Furthermore, most studies have concentrated on hepatic expression and much less is known about extrahepatic developmental events.

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

“…The human is a very interesting species with respect to developmental regulation of FMO1 and FMO3. FMO1, the major FMO in liver of most adult mammals, is expressed at relatively high concentrations in human fetal liver, but shortly after birth, expression is reduced to almost zero; the signal for termination of expression is related to the parturition and not to gestational age (Hines & McCarver, 2002;Hines et al, 2003). FMO1 may play an important role in extrahepatic drug metabolism in humans as well as in the liver of the fetus exposed to numerous potential xenobiotic substrates in utero.…”

Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects

“…We found that the top five major CYP enzymes, which are responsible for ~85% of known oxidative drug metabolism, showed activity in the hEHs, and the most important phase II glucuronidation enzymes were also active ( Figure 1G). Among these enzymes, the expression of CYP1A2 and 2C19 can only be detected well after birth in the human liver [10]. The activities of CYP3A4, 2C9, 2E1 and UGT in the hEHs were comparable to or higher than the activities in 25-week-old fetal hepatocytes.…”

Pediatric pharmacogenetic and pharmacogenomic studies: the current state and future perspectives

“…So, total CYP3A protein expression over the entire developmental period remains constant. However, because CYP3A7 and CYP3A4 exhibit differences in substrate specificity and catalytic efficacy, some differences in metabolic capacity during development are observed [8]. If is true that many genes are expressed much more in early life than in adults, is also true that many drug metabolizing enzymes (DME) are less developed in children than in adults.…”

“…Most reports on the developmental expression of DMEs have limited their studies to short time frames of development, many have depended on a small number of tissue samples, mostly confined to the hepatic expression during fetal development. Furtherome, there is also a paucity of information regarding changes during early childhood or at puberty [8]. While the pharmacogenetics as the study or clinical testing of genetic variation that gives rise to differing response to drugs might be considered similar in adults and children, the 'pharmacogenomics' as the study of how interacting systems of genes determine drug response [12] is particularly appealing in a pediatric and developmental context because this definition captures the essence of the developmental processes that characterize maturation from the time of birth through to adulthood [5].…”