scholarly journals Enantiomer Selective Glucuronidation of the Non-Steroidal Pure Anti-Androgen Bicalutamide by Human Liver and Kidney: Role of the Human UDP-Glucuronosyltransferase (UGT)1A9 Enzyme

2013 ◽  
Vol 113 (2) ◽  
pp. 92-102 ◽  
Author(s):  
Laurent Grosse ◽  
Anne-Sophie Campeau ◽  
Sarah Caron ◽  
Frédéric-Alexandre Morin ◽  
Kim Meunier ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver And Kidney ◽  
Udp Glucuronosyltransferase

scholarly journals Glucuronidation of hyodeoxycholic acid in human liver. Evidence for a selective role of UDP-glucuronosyltransferase 2B4.

1993 ◽  
Vol 268 (34) ◽  
pp. 25636-25642
Author(s):  
T Pillot ◽  
M Ouzzine ◽  
S Fournel-Gigleux ◽  
C Lafaurie ◽  
A Radominska ◽  
...  
Keyword(s):  
Human Liver ◽  
Hyodeoxycholic Acid ◽  
Udp Glucuronosyltransferase

scholarly journals Urinary Elimination of Bile Acid Glucuronides under Severe Cholestatic Situations: Contribution of Hepatic and Renal Glucuronidation Reactions

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Martin Perreault ◽  
Ewa Wunsch ◽  
Andrzej Białek ◽  
Jocelyn Trottier ◽  
Mélanie Verreault ◽  
...  
Keyword(s):  
Biliary Obstruction ◽  
Human Liver ◽  
Tandem Mass ◽  
Protein Levels ◽  
Liver And Kidney ◽  
Kidney Microsomes ◽  
Udp Glucuronosyltransferase ◽  
Serum And Urine ◽  
Serum And Urine Samples

Biliary obstruction, a severe cholestatic complication, causes accumulation of toxic bile acids (BAs) in liver cells. Glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic BAs. Using liquid chromatography coupled to tandem mass spectrometry, 11 BA glucuronide (-G) species were quantified in prebiliary and postbiliary stenting serum and urine samples from 17 patients with biliary obstruction. Stenting caused glucuronide- and fluid-specific changes in BA-G levels and BA-G/BA metabolic ratios. In vitro glucuronidation assays with human liver and kidney microsomes revealed that even if renal enzymes generally displayed lower KM values, the two tissues shared similar glucuronidation capacities for BAs. By contrast, major differences between the two tissues were observed when four human BA-conjugating UGTs 1A3, 1A4, 2B4, and 2B7 were analyzed for mRNA and protein levels. Notably, the BA-24G producing UGT1A3 enzyme, abundant in the liver, was not detected in kidney microsomes. In conclusion, the circulating and urinary BA-G profiles are hugely impacted under severe cholestasis. The similar BA-glucuronidating abilities of hepatic and renal extracts suggest that both the liver and kidney may contribute to the urine BA-G pool.

Importance of Histidine Residues for the Function of the Human Liver UDP-Glucuronosyltransferase UGT1A6: Evidence for the Catalytic Role of Histidine 370

2000 ◽  
Vol 58 (6) ◽  
pp. 1609-1615 ◽  
Author(s):  
Mohamed Ouzzine ◽  
Laurence Antonio ◽  
Brian Burchell ◽  
Patrick Netter ◽  
Sylvie Fournel-Gigleux ◽  
...  
Keyword(s):  
Human Liver ◽  
Histidine Residues ◽  
Catalytic Role ◽  
Udp Glucuronosyltransferase

scholarly journals Role of cysteine residues in the function of human UDP glucuronosyltransferase isoform 1A1 (UGT1A1)

2005 ◽  
Vol 392 (3) ◽  
pp. 685-692 ◽  
Author(s):  
Siddhartha S. Ghosh ◽  
Yang Lu ◽  
Sung W. Lee ◽  
Xia Wang ◽  
Chandan Guha ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Nucleotide Sequence Analysis ◽  
Cysteine Residues ◽  
Thiol Groups ◽  
Functional Importance ◽  
Biliary Elimination ◽  
Udp Glucuronosyltransferase

Bilirubin glucuronidation, catalysed by UGT1A1 [UGT (UDP glucuronosyltransferase) isoform 1A1, EC 2.4.1.17], is critical for biliary elimination of bilirubin. UGT1A1 deficiency causes CN-1 (Crigler–Najjar syndrome type 1), which is characterized by potentially lethal unconjugated hyperbilirubinaemia. Nucleotide sequence analysis of UGT1A1 in two CN-1 patients revealed that patient A was homozygous for a nt 530 G→A (where nt 530 G→A means guanine to adenine transition at nucleotide 530) mutation, predicting a C177Y substitution, and patient B had a nt 466 T→C mutation on one allele and a nt 1070 A→G mutation on the other, predicting a C156R and a Q357R substitution respectively. All 11 cysteine residues of mature human UGT1A1 are highly conserved in other human UGT isoforms and in rat, mouse and Rhesus monkey UGT1A1, suggesting their functional importance. Expression of mutagenized UGT1A1 plasmids showed that substitution of any of the seven cysteine residues located within the endoplasmic reticulum cisternae (including those mutated in patients A and B) abolished UGT1A1 activity or markedly increased its apparent Km for bilirubin. Substitution of the three cysteine residues within the C-terminal cytosolic tail had minimal effect on basal UGT1A1 activity, but prevented UGT1A1 activation by UDP-GlcNAc. N-Ethylmaleimide did not inhibit UGT1A1 activity in native microsomes, but prevented UGT1A1 activation by UDP-GlcNAc and inhibited the activity in digitonin-permeabilized microsomes. Dithiothreitol did not affect UGT1A1 activity in human liver microsomes. Together, the results suggested that free thiol groups, but not disulphide bonding, of seven cysteine residues within the intracisternal region of human UGT1A1 are important for its catalytic activity, while cysteine residues in the cytosolic domain may be involved in its physiological activation by UDP-GlcNAc.

scholarly journals The Insulin Receptor Mediates Insulin’s Early Plasma Clearance by Liver, Muscle, and Kidney

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 37
Author(s):  
Rick I. Meijer ◽  
Eugene J. Barrett
Keyword(s):  
Insulin Receptor ◽  
Plasma Clearance ◽  
Plasma Insulin ◽  
Insulin Clearance ◽  
Initial Plasma ◽  
Liver And Kidney ◽  
Pre Treatment ◽  
Initial Clearance

The role of the insulin receptor in mediating tissue-specific insulin clearance in vivo has not been reported. Using physiologic insulin doses, we measured the initial clearance rate (first 5 min) of intravenously injected ([125I]TyrA14)-insulin by muscle, liver, and kidney in healthy rats in the presence and absence of the insulin receptor blocker S961. We also tested whether 4 weeks of high-fat diet (HFD) affected the initial rate of insulin clearance. Pre-treatment with S961 for 60 min prior to administering labeled insulin raised plasma ([125I]TyrA14)insulin concentration approximately 5-fold (p < 0.001), demonstrating receptor dependency for plasma insulin clearance. Uptake by muscle (p < 0.01), liver (p < 0.05), and kidney (p < 0.001) were each inhibited by receptor blockade, undoubtedly contributing to the reduced plasma clearance. The initial plasma insulin clearance was not significantly affected by HFD, nor was muscle-specific clearance. However, HFD modestly decreased liver clearance (p = 0.056) while increasing renal clearance by >50% (p < 0.01), suggesting a significant role for renal insulin clearance in limiting the hyperinsulinemia that accompanies HFD. We conclude that the insulin receptor is a major mediator of initial insulin clearance from plasma and for its clearance by liver, kidney, and muscle. HFD feeding increases renal insulin clearance to limit systemic hyperinsulinemia.

Sign in / Sign up

Export Citation Format

Share Document