Functional heterogeneity of UDP-glucuronosyltransferase as indicated by its differential development and inducibility by glucocorticoids. Demonstration of two groups within the enzyme's activity towards twelve substrates

Wishart, G. J.

doi:10.1042/bj1740485

Cited by 170 publications

(64 citation statements)

References 22 publications

(13 reference statements)

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“…A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Early studies suggested that 'late fetal and neonatal clusters' of inducible rat hepatic UGT activities [74] were identical to aryl hydrocarbon-and phenobarbital-inducible UGT activities, respectively [15,16]. Induction of UGTs from low fetal UGT activities to perinatal and adult values has been reviewed [56].…”

Section: Page 9 Of 31mentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Section: Page 9 Of 31mentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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“…Two groups from the United Kingdom (Wishart 1978;Dutton & Leakey 1981;Leakey et al 1983;Coughtrie et al 1988;Scragg et al 1983Scragg et al & 1985 have performed extensive investigation of the development of hepatic UGT activity in the rat. They have demonstrated that three distinct developmental clusters of UGT activity exist.…”

Section: Glucuronidation By the Neonatal Rat Livermentioning

confidence: 99%

“…These developmental clusters are termed ''late foetal'', ''neonatal'' and ''postweaning''. The ''late foetal'' cluster of UGTs (possibly mainly UGT1 isoforms) metabolises the planar phenolic compounds (para-nitrophenol, 2-aminophenol and 1-naphthol) and develops immediately prior to birth, surging to maximal levels (above adult levels) within days before declining (Wishart 1978). Activity falls away in early infancy reaching a minimum at 13-16 days (Scragg et al 1983) before surging again to a second peak at 30-40 days.…”

Section: Glucuronidation By the Neonatal Rat Livermentioning

confidence: 99%

“…Activity falls away in early infancy reaching a minimum at 13-16 days (Scragg et al 1983) before surging again to a second peak at 30-40 days. Activity then decreases to adult levels by 70 days (Wishart 1978). The second ''neonatal cluster'' appears immediately after birth.…”

Section: Glucuronidation By the Neonatal Rat Livermentioning

confidence: 99%

“…This group includes the UGTs (possibly mainly UGT2 isoforms) that metabolise larger molecules such as bilirubin, testosterone, chloramphenicol and morphine. Activity rises steadily to reach maximal levels at about one month postpartum before falling by about 50% by adulthood (Wishart 1978). The ''post-weaning'' cluster primarily metabolise the hormone androsterone, developing rapidly after weaning at approximately 25 days.…”

Section: Glucuronidation By the Neonatal Rat Livermentioning

confidence: 99%

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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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Influence of Pesticides on UDP-glucuronosyltransferase in Rat Liver Microsomes

et al. 1996

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Fifteen pesticides, representatives of different chemical groups, were tested for their inhibitory effect on the glucuronidation of 4‐nitrophenol (4‐NP) and phenolphthalein (PPh) by rat liver microsomes. Three herbicides (simazine, chlorsulfuron, tribenuron‐methyl), two insecticides (dioxacarb, carbaryl) and one fungicide (zineb) significantly decreased the UDP‐glucuronosyltransferase (UDPGT) activity. The carbamate insecticide dioxacarb was found to be the most potent inhibitor, at 1 mM concentration suppressing 4‐NP‐UDPGT activity completely, and reducing by 55% the activity associated with the conjugation of PPh. One millimole simazine and carbaryl affected only 4‐NP glucuronidation, while chlorsulfuron and zineb exerted a marked inhibition of both 4‐NP and PPh conversion. Concentrations of 0·1 mM carbaryl, dioxacarb and zineb were still inhibitory against 4‐NP‐UDPGT, with zineb producing 40% inhibition of PPh glucuronidation. As a whole, UDPGT isoforms conjugating PPh were less sensitive to the agrochemicals tested. Kinetic studies with dioxacarb, chlorsulfuron and carbaryl revealed a mixed type of inhibition with respect to the acceptor substrate 4‐NP, with apparentKi values of 70 μM, 120 μM and 160 μM, respectively.

show abstract

Functional heterogeneity of UDP-glucuronosyltransferase as indicated by its differential development and inducibility by glucocorticoids. Demonstration of two groups within the enzyme's activity towards twelve substrates

Cited by 170 publications

References 22 publications

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Neonatal Hepatic Drug Elimination

Influence of Pesticides on UDP-glucuronosyltransferase in Rat Liver Microsomes

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