Development of multiple activities of UDP-glucuronyltransferase in human liver

Leakey, Julian E.A.; Hume, Robert; Burchell, Brian

doi:10.1042/bj2430859

Cited by 95 publications

(47 citation statements)

References 19 publications

(17 reference statements)

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“…Physiologic neonatal jaundice is associated with both an increased rate of erythrocyte turnover (41) and low levels of bilirubin UDP glucuronosyltransferase activity (42)(43)(44). The results described here suggest that decreased expression of CAR may account for the apparent failure of expression of UGT1A1 and other components of the pathway to increase in response to the increased demand.…”

Section: Discussionmentioning

confidence: 70%

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Huang

Zhang

Chua

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

361

268

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Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. Because the nuclear hormone receptor constitutive androstane receptor (CAR) mediates hepatic effects of this xenobiotic inducer, we hypothesized that CAR could be a regulator of bilirubin clearance. Activation of the nuclear hormone receptor CAR increases hepatic expression of each of five components of the bilirubin-clearance pathway. This induction is absent in homozygous CAR null mice but is observed in mice expressing human CAR instead of mouse CAR. Pretreatment with xenobiotic inducers markedly increases the rate of clearance of an exogenous bilirubin load in wild-type but not CAR knockout animals. Bilirubin itself can also activate CAR, and mice lacking CAR are defective in clearing chronically elevated bilirubin levels. Unexpectedly, CAR expression is very low in livers of neonatal mice and humans. We conclude that CAR directs a protective response to elevated bilirubin levels and suggest that a functional deficit of CAR activity may contribute to neonatal jaundice

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Section: Discussionmentioning

confidence: 70%

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Huang

Zhang

Chua

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

361

268

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“…Activity in foetal and 10 day old neonate liver tissue is generally less than 10-30% that of adult hepatic tissue. Studies of human neonatal glucuronidation involving microsomal preparations of liver samples obtained post mortem have universally demonstrated that hepatic glucuronidation in the human neonate is immature (Onishi et al 1979;Kawade & Onishi 1981;Coughtrie et al 1988;Leakey et al 1987;Burchell et al 1989).…”

Section: Glucuronidation By the Neonatal Human Livermentioning

confidence: 99%

“…However, activity to these compounds in the human neonate is only a small percentage of adult levels (Leakey et al 1987), and therefore no ''foetal cluster'' of UGT has yet been demonstrated in the human. Activity towards the substrates bilirubin, testosterone and chloramphenicol, that belong to the ''neonatal cluster'' in rats, also appears to be relatively immature in the human neonate (Kawade & Onishi 1981).…”

Section: Glucuronidation By the Neonatal Human 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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“…For human liver the existence of a distinct 5-HT isoenzyme has been postulated (39,40); based on these data the decrease of 5-HT UDPGT activity suggests that yet another isoenzyme is affected in patients A and B.…”

Section: Discussionmentioning

confidence: 97%

Immunochemical analysis of uridine diphosphate-glucuronosyltransferase in four patients with the Crigler-Najjar syndrome type I.

Es¹,

Goldhoorn²,

Paul-Abrahamse³

et al. 1990

J. Clin. Invest.

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The functional heterogeneity of uridine diphosphateglucuronosyltransferase (UDPGT) and its deficiency in human liver were investigated. The monoclonal antibody (MAb) WP1, which inhibits bilirubin and phenol-glucuronidating activity, was used to immunopurify UDPGTs from human liver. Purified UDPGTs were injected into mice to obtain new MAbs. Immunoblotting of microsomes with MAb HEB7 revealed at least three polypeptides in liver (56, 54, and 53 kD) and one in kidney (54 kD). In liver microsomes from four patients (A, B, C, and D) with Crigler-Najjar syndrome type I (CN type I), UDPGT activity towards bilirubin was undetectable (A, B, C, and D) and activity towards phenolic compounds and 5-hydroxytryptamine either reduced (A and B) or normal (C and D). UDPGT activity toward steroids was normal. Immunoblot studies revealed that the monoclonal antibody WP1 recognized two polypeptides (56 and 54 kD) in liver microsomes from patient A and none in patient B. With HEB7 no immunoreactive polypeptides were seen in these two patients. Patient C showed a normal banding pattern and in patient D only the 53-kD band showed decreased intensity. These findings suggest considerable heterogeneity with regard to the expression of UDPGT isoenzymes among CN type I patients. (J. Clin.

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Development of multiple activities of UDP-glucuronyltransferase in human liver

Cited by 95 publications

References 19 publications

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Neonatal Hepatic Drug Elimination

Immunochemical analysis of uridine diphosphate-glucuronosyltransferase in four patients with the Crigler-Najjar syndrome type I.

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