Congenital jaundice in rats due to the absence of hepatic bilirubin UDP‐glucuronyltransferase enzyme protein

Scragg, Isobel; Celier, Chantal; Burchell, Brian

doi:10.1016/0014-5793(85)80949-2

Cited by 65 publications

(17 citation statements)

References 24 publications

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“…In both fish and birds, glucuronidation is common ; however, the rates of glucuronidation of steroid hormones in plaice liver microsomes [41] and of chloramphenicol in chicken liver microsomes [15], in which substrates are glucuronidated by a family 2 isoform corresponding to UGT2B1 [30][31][32], are lower than those observed in rats. The diverse effects of oestrogenic toxicity in animals might depend on the presence or absence of the UGT isoform corresponding to UGT2B1 in the liver.…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver

Yokota

Iwano

Endo

et al. 1999

Biochemical Journal

153

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Bisphenol A, an environmental oestrogenic chemical, was found to conjugate highly with glucuronic acid in male rat liver microsomes studied in vitro. In the various isoforms tested (1A1, 1A3, 1A5, 1A6, 1A7 and 2B1), glucuronidation of bisphenol A and of diethylstilboestrol, a synthetic crystalline compound possessing oestrogenic activity and known to be glucuronidated by liver microsomes, was catalysed by an isoform of UDP-glucuronosyltransferase (UGT), namely UGT2B1, which glucuronidates some endogenous androgens. UGT activity towards bisphenol A in liver microsomes and in UGT2B1 expressed in yeast AH22 cells (22.9 and 0.58 nmol/min per mg of microsomal proteins respectively) was higher than that towards diethylstilboestrol (75.0 and 4.66 pmol/min per mg of microsomal proteins respectively). UGT activities towards both bisphenol A and diethylstilboestrol were distributed mainly in the liver but were also observed at substantial levels in the kidney and testis. Northern blot analysis disclosed the presence of UGT2B1 solely in the liver, and about 65% of the male rat liver microsomal UGT activities towards bisphenol A were absorbed by the anti-UGT2B1 antibody. These results indicate that bisphenol A, in male rat liver, is glucuronidated by UGT2B1, an isoform of UGT.

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Section: Discussionmentioning

confidence: 99%

Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver

Yokota

Iwano

Endo

et al. 1999

Biochemical Journal

153

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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%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

102

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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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“…Similarly, a single dose of MC did not induce the activity in mouse fetal liver [11]. Fetal UDPGTs have not been molecularly analyzed for any species, although fetal rat UDPGTs have been par tially characterized by electrophoretic sepa ration and immunoblot analysis [21,22], Further elucidation of the ontogeny and possible transplacental inducibility of UDPGTs is of particular interest at the present time, because cytochrome-P45o-dependent inducible fetal and maternal carcin ogen metabolism in mice has been found to be an important determinant of the transpla cental tumorigenic effect of MC [23,24]. However, phase II metabolism, leading to solubilization of carcinogen, might also be important; certainly, full understanding of fetal and maternal metabolism in relation ship to tumorigenesis by MC requires deter mination of the fate of the primary oxidized moieties.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression, Ontogeny and Transplacental Induction of Hepatic UDP-Glucuronosyl Transferase Activity in Mice

Chauhan¹,

Miller²,

Owens³

et al. 1991

Dev Pharmacol Ther

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The ontogeny and transplacental inducibility of UDP-glucuronosyl transferase (UDPGT) activities potentially relevant to detoxification of polycyclic aromatic hydrocarbons were studied in (C57BL/6 × DBA/2) F1 or (DBA/2 × C57BL/6) F1 fetal mouse liver, with p-nitrophenol (PNP) and 3-hydroxybenzo[a]pyrene (3-OH-BP) as substrates. Both UDPGT activities developed during the late fetal period and reached almost 60% of the adult activity at term; PNP, but not 3-OH-BP UDPGT decreased significantly on postnatal day 1 before rising to adult levels. A single exposure to β-naphthoflavone (βNF; 150 mg/kg) on day 17 of gestation induced the PNP-UDPGT activity significantly (1.5-fold) by day 19 in the B6D2 F1s but not D2B6 F1s. A single dose of 3-methylcholanthrene (MC; 100 mg/kg) or 2,3,7,8,-tetrachlorodibenzo-p-dioxin (10 μg/kg) did not induce, but three injections of MC also resulted in significant induction in the fetuses of C57BL/6 mothers. 3-OH-BP-UDPGT was not significantly induced by any of the chemicals in either genetic cross. In a parallel study, a gene for an inducible mouse UDPGT, designated UDPGTm^-1, was shown by Northern blotting to be expressed in fetal liver by day 18 of gestation at low levels relative to adults, but was not induced transplacentally by MC, βNF or phenobarbital (PB). These results show that (1) at least two functionally defined UDPGT activities toward phenolic substrates are present in the late fetal mouse liver; (2) one of these is transplacentally inducible by βNF and MC, but only in fetuses of C57BL/6 mothers, (3) induction where achieved was relatively small in magnitude, and (4) a gene of a PB-inducible UDPGT was expressed at low levels in the fetuses but was not induced transplacentally.

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Congenital jaundice in rats due to the absence of hepatic bilirubin UDP‐glucuronyltransferase enzyme protein

Cited by 65 publications

References 24 publications

Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver

Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver

Neonatal Hepatic Drug Elimination

Gene Expression, Ontogeny and Transplacental Induction of Hepatic UDP-Glucuronosyl Transferase Activity in Mice

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