The ontogeny of drug metabolism enzymes and implications for adverse drug events
Introduction
There is ample historical evidence from therapeutic misadventures that drug disposition and response are substantially different in children versus adults. Often cited is the administration of chloramphenicol to neonates at doses that were extrapolated from those found effective and safe in adult patients. These children exhibited symptoms referred to as grey baby syndrome consisting of emesis, abdominal distension, abnormal respiration, cyanosis, cardiovascular collapse and death. Studies subsequently demonstrated that an immature UDP glucuronosyl transferase system, resulting in impaired metabolism and clearance, was primarily responsible (Weiss et al., 1960). However, increased drug sensitivity is not universal in children versus adults. Thus, children exhibit increased resistance to acetaminophen toxicity relative to adults, apparently because of an increased capacity for sulfate conjugation early in life (Alam et al., 1977). Nevertheless, the example of chloramphenicol-induced grey baby syndrome, as well as other age-specific adverse drug events, were major impetuses for legislative changes to encourage pediatric clinical trials both in the United States (1997 FDA Modernization Act; 2002 Best Pharmaceuticals for Children Act; and the 2007 FDA Revitalization Act) and in Europe (Regulation EC No. 1901/2006 on Medicinal Products for Paediatric Use). There also has been a concerted effort to better understand life-stage-dependent changes in drug metabolism and disposition.
Changes in pharmacokinetic parameters during development (Alcorn & McNamara, 2003) contribute substantially to the differences in therapeutic efficacy and adverse drug reactions observed in children (Kearns et al., 2003a). Of these parameters, changes in drug metabolizing enzyme (DME) expression, as exemplified by the example of grey baby syndrome described above, are recognized as making a major contribution to the overall pharmacokinetic differences between adults and children (Hines and McCarver, 2002, McCarver and Hines, 2002). However, the knowledge needed to better understand and more importantly, predict therapeutic dosing and avoidance of adverse reactions during maturation remains incomplete. This gap in knowledge is despite the increasing prescription of off-label medications for pediatric diseases based on adult efficacy data, particularly in the neonatal and pediatric intensive care settings (Cuzzolin et al., 2006). Advances in human developmental pharmacology that would address this knowledge gap have faced several challenges. Of major importance have been ethical and logistical problems in obtaining suitable tissue samples for in vitro studies. Increasing the significance of these problems was the realization that substantial species differences exist in both DME primary structure and regulatory mechanisms, causing concern regarding the ability to readily extrapolate data from animal model systems to humans. Furthermore, dynamic changes in gene expression occur during different stages of ontogeny. Thus, the common study design involving a small number of tissue samples representing a narrow time window, or the pooling of samples across large windows of time, has lead to data from which definitive conclusions are difficult to make. The science also has been hampered by the promiscuous nature of many of the DME making it difficult to identify specific probe substrates or develop highly specific antibodies. Questions regarding the cross-reactivity of antibodies raised against animal model antigens also have been raised. In addition, the lack of appreciation of the complexity of some of the loci encoding human DMEs has lead to the utilization of non-specific probes, and the mis-belief that transcript levels would correlate well with protein and activity levels [see Rich and Boobis (1997) for a discussion of many of these latter points].
The objective of this review is to summarize our current knowledge regarding the ontogeny of key human hepatic enzymes that potentially impact xenobiotic pharmacokinetics and indirectly, pharmacodynamics. The review also will try to put this knowledge into the context of other developmental changes that have a significant impact on pharmacokinetics.
Section snippets
Physiological factors impacting drug disposition during development
Several physiological parameters undergo changes during development that can impact drug disposition [see Kearns et al. (2003a) for a recent review]. For example, intragastric pH is elevated in the neonate relative to later life stages resulting in lower bioavailability of weakly acidic drugs. Maturation of intestinal motor activity takes place during early infancy and also impacts drug absorption. Similar to what has been observed in the liver, intestinal enzymes and transporters that
Metabolic factors impacting drug disposition during development
Several groups demonstrated low-level expression of one or more cytochromes P450 early in fetal liver development using either probe substrates (Cresteil et al., 1982, Pasanen et al., 1987, Lee et al., 1991), fractionation and purification (Cresteil et al., 1982), western blotting (Kitada et al., 1991), and/or by reverse transcriptase-coupled polymerase chain reaction (RT-PCR) DNA amplification (Hakkola et al., 1994). However, all of these approaches were limited by their specificity and many
Epoxide hydrolase (EPHX)
Although several mammalian EPHX (EC 3.3.2.3) exist, two are known for their important role in detoxifying often highly reactive xenobiotic epoxides by the addition of water to form dihydrodiols, microsomal epoxide hydrolase (EPHX1) and soluble epoxide hydrolase (EPHX2). More recently, EPHX2 also has been recognized for its critical role in the inactivation of epoxyeicosatrienoic acid signaling molecules that exhibit potent vasodilatory, antiinflammatory, and fibrinolytic effects. As such, EPHX2
Cell-specific expression and ontogeny
In the human fetus, the liver is the major site of multilineage hematopoiesis with initial activity detectable by five weeks gestation, maximal activity by 15 weeks gestation, and then a decline and eventual disappearance of activity at or around birth. During the peak of this activity, hematopoietic stem cells and precursors account for nearly 50% of the total cells in the developing liver. This is in contrast to the adult and even perinatal liver where parenchymal hepatocytes dominate (
Regulation of drug metabolizing enzyme ontogeny
Knowledge regarding specific mechanisms regulating the developmental expression of the DME genes is extremely limited. Factors regulating the ontogeny of the class 1 ADH genes (ADH1A, ADH1B, and ADH1C) have been reviewed by Edenberg (2000). All of the class 1 ADH contain TATA boxes within their basal promoters. All three of these genes also contain a CCAAT/enhancer binding protein (C/EBP) element between the TATA box and the transcription start site that is capable of binding both C/EBPα and
Summary and conclusions
Although oversimplified, the ontogeny of individual DME can be categorized into one of three groups. As typified by CYP3A7, FMO1, SULT1A3/4, SULT1E1, and perhaps ADH1A, some enzymes are expressed at their highest level during the first trimester and either remain at high concentrations, or decrease during gestation, but are silenced or expressed at low levels within one to two years after birth. An obvious question is whether or not these enzymes have an important endogenous function during
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