Developmental pharmacology and toxicology: biotransformation of drugs and other xenobiotics during postnatal development.
The following conclusions can be drawn: Depending on reaction type, species (strain), organ (tissue) and sex (in rats and mice) both phase I and phase II ractions show developmental patterns with maximum activities in juvenile or young adult animals. In man drug disposition in newborns is also generally much lower than in children and young adults. Mammals with long gestation periods are born with considerable activities and adult values are reached earlier than in animals with short gestation periods. Highest activities (with very few exceptions) are observed in liver postnatally. With increasing age, in all laboratory animals and in man, a decline of biotransformation capacity is observed. Most of these reactions are inducible by inducers of the phenobarbital-, 3-methylcholanthrene- and tetrachlorodibenzo-p-dioxine-, steroid- or alcohol-type. Inducibility also depends on reaction type, species (strain), organ (tissue) and sex (in rats and mice). Inducibility begins in the earliest embryonic stage and reaches high rates in species with long gestation periods before birth, and at or after birth in species with short gestation periods. The beginning of high inducibility depends also on inducer types and the induced parameter. Inducible reactions can be increased in immature as well as in very old animals up to or above the level of adult animals. Isozymes may show different developmental patterns and inducibilities. Development and induction of isozymes catalyzing different reactions can be triggered in clusters. There is increasing evidence that basic biotransformation activities as well as their inducibilities by foreign compounds are essentially influenced by a kind of temporal genetic control during the whole life span. When we compared different monooxygenase reactions and their inducibility (Klinger et al., 1968) both the presence of P450 isozymes and their different inducibility as well as their different developmental pattern became evident, the direct proof of which was given 10 years later by the Nebert group (Atlas et al. 1977). Functional heterogeneity was demonstrated by differential development and inducibility by glucocorticoids also for UDP-glucuronosyl transferase (Wishart, 1978): in the rat the increased fetal glucocorticoid activity between days 17 and 20 of gestation triggers the surge to adult or higher than adult activities. This cluster of the so-called late fetal glucuronyltransferase group is distinctly different from the neonatal or postnatal cluster with peak values after birth and a pronounced inducibility by 3-methylcholanthrene, but not by steroids. These different transferase clusters can be differentiated by different substrates, too. To get an overview on the postnatal development of the most important phase I and phase II reactions and also for the heme biosynthetic pathway as a prerequisite for the P450 synthesis, a compilation of literature data similar to a score was constructed with the aim to recognize parallel developments, possible common control and regulation mechanisms, cp. Klinger et al. 1987, cp. also Figs. 1-3. Evidently different developmental patterns can be observed, direct connections or dependencies cannot be detected. Thus different concentrations resp. activities of different P450 forms during ontogenetic development are influenced by many factors on the transscriptional and posttransscriptional level. Reviews on concepts and therories of development and aging have been published by several authors respectively editors (cp. Klinger, 1996). But there is no convincing concept or proof on the molecular-biological basis of an internal clock which regulates and controls individual development, aging and death.
Klinger
Wolfgang
W
Institute of Pharmacology and Toxicology Friedrich Schiller University Jena, Jena, Germany.
D000367:Age Factors; D000818:Animals; D001711:Biotransformation; D004790:Enzyme Induction; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D015262:Xenobiotics / Q000493:pharmacokinetics*
D015262:Xenobiotics