Regulation of onset of development of UDP-glucuronosyltransferase activity towards <i>o</i>-aminophenol by glucocorticoids in late-foetal rat liver <i>in utero</i>

Wishart, G. J.; Dutton, Geoffrey J.

doi:10.1042/bj1680507

Cited by 32 publications

(7 citation statements)

References 18 publications

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“…This dexamethasone-induced precocious fluidization of the fetal-rat liver microsomal membrane suggests that endogenous glucocorticoids play a major role in the perinatal processes leading to membrane fluidization. Similarly, dexamethasone administration to pregnant rats before the natural surge of fetal corticosteroids, precociously induced the synthesis of microsomal UDP-glucuronosyltransferase in fetal-rat liver (Wishart & Dutton, 1977). Thus glucocorticoids appear to be involved not only in regulating the perinatal synthesis of microsomal enzymes, but also in controlling the formation of the membranes of the smooth endoplasmic reticulum of rat liver, and may therefore play an important role in modulating the activity of these newly synthesized enzymes.…”

Section: Relative Content (%)mentioning

confidence: 95%

Glucocorticoids increase the fluidity of the fetal-rat liver microsomal membrane in the perinatal period

Kapitulnik¹,

Weil²,

Rabinowitz³

1986

Biochemical Journal

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Dexamethasone, a synthetic glucocorticoid, was administered to pregnant rats during the last week of pregnancy in order to examine its effects on the fluidity of the developing fetal-rat liver microsomal membrane. This early prenatal exposure to dexamethasone, which preceded the natural appearance of fetal corticosteroids, markedly accelerated the normal perinatal course of fluidization of this membrane. The lipid apparent microviscosity, which was determined by measurement of fluorescence polarization, decreased in 21-days-old treated fetuses to values that were indistinguishable from those of untreated newborn rats. This dexamethasone-mediated acceleration of membrane fluidization was associated with an increase in the index of unsaturation of the fatty acyl moiety of microsomal lipids. Dexamethasone caused a significant increase in the microsomal content of polyunsaturated fatty acids (arachidonic and linoleic acid), which was accompanied by a decrease in content of monoenoic fatty acids (oleic and palmitoleic acid). This early exposure in utero to dexamethasone precociously induced the changes in fatty acid composition of fetal-rat liver microsomal lipids that normally occur between the last day of pregnancy and the first day of extra-uterine life. These results suggest that endogenous glucocorticoids play a major role in the perinatal fluidization of the rat liver microsomal membrane.

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Section: Relative Content (%)mentioning

confidence: 95%

Glucocorticoids increase the fluidity of the fetal-rat liver microsomal membrane in the perinatal period

Kapitulnik¹,

Weil²,

Rabinowitz³

1986

Biochemical Journal

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“…The existence of such distinct developmental patterns is suggestive of different UGT genes being subject to differential regulation during the perinatal period. Maternally administered glucocorticosteroid triggers the maturation of the ''foetal cluster'' of UGTs in the rat (Wishart & Dutton 1977), but not the ''neonatal cluster'' (Wishart 1978). After birth the ''neonatal cluster'' becomes competent to respond to corticosteroid treatment with induction of UGT activity (Leakey 1984).…”

Section: Glucuronidation By the Neonatal Rat Livermentioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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“…This correlation is strengthened by the observation that UDP-glucuronosyltransferases did not rise after decapitation in utero. 15 So, the perinatal onset of this enzyme appears to require corticosterone in vivo. In another set of experiments, designed to delineate the regulating effect of glucocorticoids, litters already exposed to the physiological level of circulating corticoids, received exogenous steroids at a pharmacological concentration.…”

Section: Ontogenesis and Regulation Of Other Drug-metabolizing Enzymementioning

confidence: 99%

Regulation of drug‐metabolizing enzymes during the perinatal period in rat and human liver

Cresteil

1987

BioEssays

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The importance of drug‐metabolizing enzymes in developing mammals has been recently reevaluated in view of the activities and potential inducibilities of these enzymes. The role of endogenous factors raises the question of whether there is a positive regulation of the expression of drug‐metabolizing enzymes by hormones. In humans, among the different isoenzymes of cytochrome P‐450 described in adult liver, only one is absent in 20‐week‐old fetuses. Epoxide hydrolase and glutathione S‐transferases are active while UDP‐glucuronidation develops postnatally. The consequence of this asynchronous rise of activities is briefly discussed.

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Regulation of onset of development of UDP-glucuronosyltransferase activity towards o-aminophenol by glucocorticoids in late-foetal rat liver in utero

Cited by 32 publications

References 18 publications

Glucocorticoids increase the fluidity of the fetal-rat liver microsomal membrane in the perinatal period

Glucocorticoids increase the fluidity of the fetal-rat liver microsomal membrane in the perinatal period

Neonatal Hepatic Drug Elimination

Regulation of drug‐metabolizing enzymes during the perinatal period in rat and human liver

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