Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The urinary excretion of D-glucaric acid, a catabolite of glucuronic acid, is considered to be a reliable index of the state of hepatic microsomal enzyme activity. Because enzyme activity may be altered in liver disease, we examined the effect of liver disease on the excretion of this metabolite and its correlation with liver function tests. We studied 89 patients with nonhemolytic jaundice, 39 with viral hepatitis, 33 with obstructive jaundice, six with cirrhosis, and 11 patients with jaundice of mixed etiology. Glucaric acid excretion was significantly increased in all these patients as compared to controls, most pronounced in the obstructive jaundice group. No correlation was found between glucaric acid excretion and concentrations of bilirubin, albumin, globulin, aspartate aminotransferase, alkaline phosphatase, cholesterol, or gamma-glutamyltransferase in serum, even though the concentrations of these analytes did vary with the type of liver disease. We suggest that this increase in glucaric acid excretion is an indication of normal or even increased glucuronidation (UDP-glucuronosyltransferase activity), which occurs in liver disease.
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PMID:Increased D-glucaric acid excretion by jaundiced patients. 69 85

Microsomal UDP-glucuronosyltransferase activity toward the bile acids (chenodeoxycholic, deoxycholic, ursodeoxycholic, lithocholic, and glycolithocholic) has been detected in human specimens of liver, kidney, and intestinal mucosa. The characteristics of hepatic and extrahepatic UDP-glucuronosyltransferase activities toward these bile acids were compared with respect to kinetic parameters and other catalytic properties. Whereas no organ-specific differences in the affinities of individual bile acids to hepatic and extrahepatic UDP-glucuronosyltransferases were observed, the individual bile acids showed reaction rates in liver that were about twice the rates estimated in kidney and about twice to three times the rates observed in duodenal mucosa. In intestinal mucosa the rate of chenodeoxycholic acid glucuronidation exhibited a progressive decrease from duodenum to colon, where it was 30% of the duodenal level. Comparison of the glucuronidation rates that were estimated with different bile acids in hepatic or extrahepatic tissues showed that for each organ a bile acid structure-activity relationship existed, with highest activity observed for lithocholic and ursodeoxycholic acids, which was about twofold higher compared with chenodeoxycholic or deoxycholic acids. Lowest activity was estimated for glycolithocholic acid. UDP-glucuronosyltransferase activity toward chenodeoxycholic acid was studied in biopsy specimens of liver that were obtained from a large group of patients with the following liver diseases: liver cirrhosis, liver fibrosis, granulomatous hepatitis, fatty liver hepatitis, and fatty liver. A significant decrease in enzyme activity was observed in patients with liver cirrhosis and in patients with granulomatous hepatitis compared with patients without liver disease.
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PMID:Hepatic and extrahepatic glucuronidation of bile acids in man. Characterization of bile acid uridine 5'-diphosphate-glucuronosyltransferase in hepatic, renal, and intestinal microsomes. 643 Sep 60

In patients with cirrhosis, the elimination of drugs metabolized by glucuronidation is relatively preserved, in comparison with the metabolism of drugs by oxidation. This study explores this phenomenon at a molecular level. In cirrhotic rat livers the content of UDP-glucuronosyltransferase (UGT) was examined by immunohistochemistry and immunoblotting using three antibodies: (i) a polyclonal antibody directed against a broad number of UGT isoforms from both family 1 and family 2; (ii) a family 2-specific antibody; and a (iii) family 1-specific antibody. The steady state mRNA level of UGT of a family 2 isoform was also detected by northern blot analysis. The results demonstrate normal or increased UGT protein by immunohistochemistry and immunoblot in cirrhotic livers compared with controls. This was accompanied by increased steady state mRNA encoding the UGT isoform UGT2B1. In contrast, an isoform of cytochrome P450 (CYP2C11) was reduced markedly in both immunohistochemical staining and immunoblot analysis. These results suggest that in cirrhosis there is a comparative increase or at least a maintenance of UGT enzyme content and that this most likely occurs at a pretranslational level.
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PMID:UDP glucuronosyltransferase in the cirrhotic rat liver. 871 5

Pharmacokinetic studies demonstrated that the decrease in drug biotransformation in hepatic failure depends on the metabolic pathways involved. To test whether glucuronidation reactions supported by UDP-glucuronosyltransferases are differentially affected in such conditions, we investigated the in vitro glucuronidation of four selected drugs and xenobiotics (zidovudine, oxazepam, lamotrigine, and umbelliferone) by using microsomes from human healthy and unhealthy (cirrhosis, hepatitis) livers as enzyme sources. Theses substances are glucuronidated by several UDP-glucuronosyltransferase isoforms. Lidocaine N-deethylation activity measured concomitantly was used as a positive control, because the inhibition of this reaction in patients with hepatic diseases is well documented. The metabolic clearances of zidovudine and lidocaine were decreased significantly in liver cirrhosis (0.17 versus 0.37 microliter/min/mg protein and 0.40 versus 2.73 microliter/min/mg protein, respectively) as a consequence of a decrease of their corresponding Vmax of metabolism. By contrast, the metabolic clearances of oxazepam, umbelliferone, and lamotrigine glucuronidation remained unchanged. Previous studies reported that the in vivo oral clearances of zidovudine and lidocaine were decreased by 70% and 60%, respectively, in cirrhotic livers, whereas those of lamotrigine and oxazepam were not affected. Consequently, it is likely that the in vitro metabolic data, which support the in vivo results, therefore could contribute to reasonably predict the level of impairment of hepatic clearance in patients with liver cirrhosis.
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PMID:Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. 1021 1

Variations in the UDP-glucuronosyltransferase (UGT) 1A7 gene have been found to be related to the development of hepatocellular carcinoma (HCC). Since the pathogenesis of liver cirrhosis is not dissimilar to that of HCC, we hypothesized that UGT1A7 genetic polymorphisms may be associated with liver cirrhosis. PCR-restriction fragment length polymorphism was utilized to determine UGT for 1A7 genotypes for the 159 patients with liver cirrhosis and 263 gender/age matched controls. Simple logistic regression analysis revealed that significant risk factors for liver cirrhosis were (1) hepatitis B virus (HBV) infection, (2) hepatitis C virus (HCV) infection, (3) HBV infection plus HCV infection and (4) low-activity UGT1A7 genotypes. The results of further multivariate logistic regression confirmed these associations. Interaction of low-activity UGT1A7 genotypes and HBV (or HCV) infection produced an additive effect upon the risk for the development of liver cirrhosis [observed odds ratio (OR) (54.59) greater than the expected OR (18.05)]. UGT1A7 low/low genotype was also related to advanced liver cirrhosis (Child-Pugh classes C and/or B) (OR=7.50, P=0.009). This study demonstrates the novel findings that carriage of low-activity UGT1A7 genotypes represents a risk factor for the development and functional severity of liver cirrhosis.
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PMID:UDP-glucuronosyltransferase 1A7 polymorphisms are associated with liver cirrhosis. 1805 30

Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5- to 2.5-fold and 2.5- to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.
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PMID:Thioacetamide intoxication triggers transcriptional up-regulation but enzyme inactivation of UDP-glucuronosyltransferases. 2173 83

The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 3'-phosphoadenosine-5'-phosphosulfate synthase 1 were increased in NASH (not fatty/cirrhosis) only. UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD.
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PMID:Altered UDP-glucuronosyltransferase and sulfotransferase expression and function during progressive stages of human nonalcoholic fatty liver disease. 2322 17