Paracetamol glucuronidation by recombinant rat and human phenol UDP-glucuronosyltransferases

Bock, Karl Walter; Forster, Adelheid; Gschaidmeier, Harald; Brück, Monika; Münzel, Peter A.; Schareck, W.; Fournel‐Gigleux, Sylvie; Burchell, Brian

doi:10.1016/0006-2952(93)90437-2

Cited by 120 publications

(52 citation statements)

References 22 publications

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“…It is possible that the combined low turnover by two or more isozymes is equivalent to the high turnover by a single isozyme and, no doubt, ensures detoxification. Although widely used acetaminophen was shown in earlier studies to undergo conversion primarily by UGT1A6 (27), a recent report indicates that UGT1A9 and other isozymes are also important to its glucuronidation and that it is converted by different isozymes under different conditions (28). Our studies indicate that both UGT1A6 (24) and UGT1A9 2 metabolize acetaminophen nearly equally and at relatively low rates compared with their other substrates.…”

Section: Glucuronidation Of Simple and Polycyclic Phenols By Human Ugtsmentioning

confidence: 99%

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Basu¹,

Ciotti²,

Hwang

et al. 2004

Journal of Biological Chemistry

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UDP-glucuronosyltransferase (UGT) isozymes detoxify metabolites, drugs, toxins, and environmental chemicals via conjugation to glucuronic acid. Based on the extended UGT1 locus combined with Northern blot analysis and in situ hybridization, we determined the distribution of UGT1A1 and UGT1A7 through UGT1A10 mRNAs and found them for the first time segmentally distributed in the mucosal epithelia layer of the gastrointestinal tract. Biochemically, recombinant isozymes exhibited pH optima of 5.5, 6.4, 7.6, 8.5, and/or a broad pH range, and activities were found to be unaffected or progressively inhibited by increasing substrate concentrations after attaining V max for certain chemicals. Under different optimal conditions, all exhibited wide substrate selections for dietary and environmentally associated chemicals. Evidence also suggests tandem effects of isozymes in the time for completion of reactions when comparing short-and long-term incubations. Moreover, treatment of colon cells with certain dietassociated constituents, curcumin and nordihydroguaiaretic acid, reversibly targets UGTs causing inhibition without affecting protein levels; there is no direct inhibition of control UGT using curcumin as substrate in the in vitro assay. In summary, we demonstrate that UGTs are located in gastrointestinal mucosa, have vast overlapping activities under differential optimal conditions, and exhibit marked sensitivity to certain dietary substrates/constituents, representing a first comprehensive study of critical properties concerning glucuronidating isozymes in alimentary tissues. Additionally, the highly dynamic, complex, and variable properties necessarily impact absorption of ingested chemicals and therapeutic drugs.The gastrointestinal (GI) 1 system has the critical function of absorbing nutrients from the diet and, simultaneously, acting as a barrier to ingested toxins and unwanted chemicals. To this end, the human UGT1 complex locus, which encodes multiple UDP-glucuronosyltransferase (UGT) isozymes distributed in the GI tract, participates in the broad and critical function of detoxifying lipid-soluble phenols derived metabolically or ingested as part of the diet, its contaminants, and as medications. UGT conjugates glucuronic acid to the acceptor substrate, converting the lipophile to an inactive glucuronide that undergoes facilitated excretion. The isozymes metabolize endogenous substrates such as bilirubin, steroids, bile acids, retinoic acid, and thyroid hormones. Equally important, isozymes also metabolize four categories of dietary phytochemicals that could pose risks for humans and animals when absorbed in excess. Highly abundant dietary flavonoids found in plants are shown to inhibit aromatase (1), and less abundant anthraquinones and two types of phytoestrogens (2-4) can also cause cellular damage. Particular anthraquinones were mutagenic when bioactivated (3) and were carcinogens in long-term feeding experiments in mice (5). Injurious effects of diets were demonstrated by extensive lesions in the reprodu...

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Section: Glucuronidation Of Simple and Polycyclic Phenols By Human Ugtsmentioning

confidence: 99%

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Basu¹,

Ciotti²,

Hwang

et al. 2004

Journal of Biological Chemistry

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“…Metabolism of paracetamol is primarily by conjugation to form paracetamol glucuronide and paracetamol sulfate. Glucuronidation is catalysed by UGT1A6 and to a lesser extent by UGT1A9 (Bock et al 1993;Ciotti et al 1997). Surprisingly, given its general use, there have been no large studies investigating the pharmacokinetics of paracetamol in the neonatal period; clearance data of paracetamol in neonates is very limited and most information comes from urinary excretion studies after oral dosage.…”

Section: Paracetamolmentioning

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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“…UGT1A6 is a human isoform encoded by the UGT1 locus, which is expressed predominantly in the liver but also in kidney and other extrahepatic tissues [7]. It is responsible for the conjugation of planar phenols such as 4-methylumbelliferone (4-MU), drugs (paracetamol, naftazone [8,9]) or environmental carcinogens such as chrysene and benzo[a]pyrene derived phenols [10]. The individual specificity of each UGT isoform towards aglycone substrates is provided by the N-terminal domain that represents the major region of dissimilarity between UGTs [11].…”

Section: Introductionmentioning

confidence: 99%

Expression of a functionally active human hepatic UDP‐glucuronosyltransferase (UGT1A6) lacking the N‐terminal signal sequence in the endoplasmic reticulum

et al. 1999

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UDP-glucuronosyltransferase 1A6 (UGT1A6) is a membrane glycoprotein of the endoplasmic reticulum playing a key role in drug metabolism. It is synthesized as a precursor with an N-terminal cleavable signal peptide. We demonstrate that deletion of the signal peptide sequence does not prevent membrane targeting and integration of this human isoform when expressed in an in vitro transcription-translation system, as shown by N-glycosylation, resistance to alkaline treatment and protease protection. Furthermore, UGT1A6 lacking the signal peptide (UGT1A6Asp) was targeted to the endoplasmic reticulum in mammalian ceils as shown by immunofluorescence microscopy and was catalytically active with kinetic constants for 4-methylumbelliferone glucuronidation similar to that of the wildtype. These results provide evidence that the signal peptide is not essential for the membrane assembly and activity of UGTIA6 suggesting that additional topogenic element(s) mediate(s) this process.

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Paracetamol glucuronidation by recombinant rat and human phenol UDP-glucuronosyltransferases

Cited by 120 publications

References 22 publications

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Neonatal Hepatic Drug Elimination

Expression of a functionally active human hepatic UDP‐glucuronosyltransferase (UGT1A6) lacking the N‐terminal signal sequence in the endoplasmic reticulum

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