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)

Thioacetamide (TAA) administration is an established technique for generating rat models of liver fibrosis and cirrhosis. Oxidative stress is believed to be involved as TAA-induced liver fibrosis is initiated by thioacetamide S-oxide, which is derived from the biotransformation of TAA by the microsomal flavine-adenine dinucleotide (FAD)-containing monooxygense (FMO) and cytochrome P450 systems. A two-dimensional gel electrophoresis-mass spectrometry approach was applied to analyze the protein profiles of livers of rats administered with sublethal doses of TAA for 3, 6 and 10 weeks respectively. With this approach, 59 protein spots whose expression levels changed significantly upon TAA administration were identified, including three novel proteins. These proteins were then sorted according to their common biochemical properties and functions, so that pathways involved in the pathogenesis of rat liver fibrosis due to TAA-induced toxicity could be elucidated. As a result, it was found that TAA-administration down-regulated the enzymes of the primary metabolic pathways such as fatty acid beta-oxidation, branched chain amino acids and methionine breakdown. This phenomenon is suggestive of the depletion of succinyl-CoA which affects heme and iron metabolism. Up-regulated proteins, on the other hand, are related to oxidative stress and lipid peroxidation. Finally, these proteomics data and the data obtained from the scientific literature were integrated into an "overview model" for TAA-induced liver cirrhosis. This model could now serve as a useful resource for researchers working in the same area.
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PMID:A proteomic analysis of thioacetamide-induced hepatotoxicity and cirrhosis in rat livers. 1552 43

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance. This fact, as well as the discovery of the proliferation of the smooth endoplasmic reticulum (SER) after chronic alcohol consumption, suggested the existence of an additional pathway which was then described by Lieber and DeCarli, namely the microsomal ethanol oxidizing system (MEOS), involving cytochrome P450. The existence of this system was initially challenged but the effect of ethanol on liver microsomes was confirmed by Remmer and his group. After chronic ethanol consumption, the activity of the MEOS increases, with an associated rise in cytochrome P450, especially CYP2E1, most conclusively shown in alcohol dehydrogenase negative deer mice. There is also cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, the conversion of hepatotoxic agents to toxic metabolites increases, which explains the enhanced susceptibility of alcoholics to the adverse effects of various xenobiotics, including industrial solvents. CYP2E1 also activates some commonly used drugs (such as acetaminophen) to their toxic metabolites, and promotes carcinogenesis. In addition, catabolism of retinol is accelerated resulting in its depletion. Contrasting with the stimulating effects of chronic consumption, acute ethanol intake inhibits the metabolism of other drugs. Moreover, metabolism by CYP2E1 results in a significant release of free radicals which, in turn, diminishes reduced glutathione (GSH) and other defense systems against oxidative stress which plays a major pathogenic role in alcoholic liver disease. CYP1A2 and CYP3A4, two other perivenular P450s, also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. CYP2E1 has also a physiologic role which comprises gluconeogenesis from ketones, oxidation of fatty acids, and detoxification of xenobiotics other than ethanol. Excess of these physiological substrates (such as seen in obesity and diabetes) also leads to CYP2E1 induction and nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), with pathological lesions similar to those observed in alcoholic steatohepatitis. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP2E1 up-regulation was also demonstrated in obese patients as well as in rat models of obesity and NASH. Furthermore, NASH is increasingly recognized as a precursor to more severe liver disease, sometimes evolving into "cryptogenic" cirrhosis. The prevalence of NAFLD averages 20% and that of NASH 2% to 3% in the general population, making these conditions the most common liver diseases in the United States. Considering the pathogenic role that up-regulation of CYP2E1 also plays in alcoholic liver disease (vide supra), it is apparent that a major therapeutic challenge is now to find a way to control this toxic process. CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds are too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated phosphatidylcholines extracted from soybeans (and its active component dilinoleoylphosphatidylcholine), were discovered to decrease CYP2E1 activity. PPC also opposes hepatic oxidative stress and fibrosis. It is now being tested clinically.
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PMID:The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. 1555 33

Mutation of the cytoskeletal intermediate filament proteins keratin 8 and keratin 18 (K8/K18) is associated with cirrhosis in humans, whereas transgenic mice that overexpress K18 Arg89-->Cys (R89C) have significant predisposition to liver injury. To study the mechanism of keratin-associated predisposition to liver injury, we used mouse microarrays to examine genetic changes associated with hepatocyte keratin mutation and assessed the consequences of such changes. Liver gene expression was compared in R89C versus nontransgenic or wild-type K18-overexpressing mice. Microarray-defined genetic changes were confirmed by quantitative polymerase chain reaction. Nineteen genes had a more than two-fold altered expression (nine downregulated, 10 upregulated). Upregulated genes in keratin-mutant hepatocytes included the oxidative metabolism genes cytochrome P450, S-adenosylhomocysteine (SAH) hydrolase, cysteine sulfinic acid decarboxylase, and oxidation-reduction pathway genes. Downregulated genes included fatty acid binding protein 5, cyclin D1, and some signaling molecules. Several methionine metabolism-related and glutathione synthetic pathway intermediates, including S-adenosylmethionine (SAMe) and SAH, were modulated in R89C versus control mice. R89C livers had higher lipid and protein oxidation by-products as reflected by increased malondialdehyde and oxidized albumin. In conclusion, K18 point mutation in transgenic mice modulates several hepatocyte oxidative stress-related genes and leads to lipid and protein oxidative by-products. Mutation-associated decreases in SAH and SAMe could compromise needed cysteine availability to generate glutathione during oxidative stress. Hence keratin mutations may prime hepatocytes to oxidative injury, which provides a new potential mechanism for how keratin mutations may predispose patients to cirrhosis.
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PMID:Keratin mutation primes mouse liver to oxidative injury. 1572 65

BALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism (Alas1 and Hmox1, respectively) were only modestly affected even in the presence of the cytochrome P450-inducing CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. In contrast, in BALB/c mice exhibiting griseofulvin-induced hepatic protoporphyria with induction and destruction of cytochrome P450, both Alas1 and Hmox1 genes were markedly up-regulated. Other expression profiles in BALB/c Fech(m1Pas) mice identified roles for oxidative mechanisms in liver injury while modulated gene expression of hepatocyte transport proteins and cholesterol and bile acid synthesis illustrated the development of cholestasis. Subsequent inflammation and cirrhosis were also shown by the up-regulation of cytokine, cell cycling, and procollagen genes. Thus, gene expression profiles studied in Fech(m1Pas) mice may provide candidates for human polymorphisms that explain the sporadic hepatic consequences of erythropoietic protoporphyria.
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PMID:Hepatic gene expression in protoporphyic Fech mice is associated with cholestatic injury but not a marked depletion of the heme regulatory pool. 1579 85

To study whether chronic liver disease (CLD) and genetic polymorphism affect the hepatic activity of cytochrome P450 (CYP) isoforms, we compared in vivo CYP2C19 and CYP3A activities using 3-hour omeprazole hydroxylation index (plasma concentration ratio of omeprazole to its 5-hydroxylated metabolite; a higher index indicates lower CYP2C19 activity) and partial formation clearance of cortisol to 6beta-hydroxycortisol (CL(cortisol-->6beta-HC)) in 31 CLD patients (9 with chronic hepatitis; 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, and 1 type C) and 30 healthy subjects with different CYP2C19 genotypes. The mean (+/-SEM) omeprazole hydroxylation index in CLD patients with homozygous extensive metabolizer (EM) genotype (*1/*1, n = 8), heterozyous EM (*1/*2, n = 11; *1/*3, n = 6) genotypes and poor metabolizer (PM) genotypes (*2/*2, n = 3; *3/*3, n = 3) were 17.15 +/- 2.12, 20.02 +/- 2.63, and 26.04 +/- 3.15, respectively, which were significantly higher compared with control subjects with the corresponding CYP2C19 genotypes (0.81 +/- 0.09, 1.55 +/- 0.20, and 15.5 +/- 1.52). CLD patients with PM genotype had significantly (P < .05) higher omeprazole hydroxylation indexes than did those with homozygous EM genotype, and those with heterozygous EM genotypes had intermediate values. The mean CL(cortisol-->6beta-HC) decreased significantly (P < .001) in CLD patients compared with control subjects (1.19 +/- 0.12 versus 2.26 +/- 0.24 mL/min). Multiple regression analysis showed that CLD, serum albumin level, and CYP2C19 genotype correlated significantly (P < .05) with the omeprazole hydroxylation index, whereas no significant correlation was observed between CL(cortisol-->6beta-HC) and other variables, except CLD. Because CLD and genetic polymorphism of CYP2C19 act additively to reduce CYP2C19 activity, genotyping these patients may be of value in averting adverse reactions of drugs that depend on CYP2C19 for elimination.
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PMID:In vivo metabolic activity of CYP2C19 and CYP3A in relation to CYP2C19 genetic polymorphism in chronic liver disease. 1623 54

1. Noninvasive tests for the staging of chronic hepatitis C virus (HCV) infection would be an attractive alternative to liver biopsy. The 13C-aminopyrine breath test (ABT) has been proposed for the noninvasive assessment of hepatic function and partly correlates with fibrosis. We aimed to investigate causes for the lack of discriminatory power for different degrees of hepatic fibrosis. 2. Eighty-three patients (median age 49 years (28-78 years)) with chronic HCV infection underwent the ABT after an oral load of 75 mg N,N-dimethyl-13C-aminopyrine. Portal vein flow was assessed by duplex-Doppler and a laboratory index (aspartate aminotransferase to platelet ratio index or APRI) was calculated. Parameters were compared with liver histology. 3. The cumulative 13C-recovery differed significantly between patients without relevant fibrosis (fibrosis score 0-2) and cirrhosis (5-6), beginning after 30 min of sampling (P < 0.05). The ABT did not discriminate patients with fibrosis scores 3-4 from the remaining two patient groups. Sensitivity and specificity for the prediction of cirrhosis was 73.4-82.8% and 63.2-68.4%, depending on the sampling time. Compared with the fibrosis score (P = 0.04), patient age was a highly significant independent predictor for the 13C-recovery (P < 0.0001). Aspartate aminotransferase to platelet ratio index and duplex-Doppler predicted cirrhosis with 76.6%vs. 87.5% sensitivity and 63.2%vs. 68.4% specificity. 4. Our data suggest an age-dependent decrease of cytochrome P450 activity which probably accounts for the large overlap of ABT results that preclude clear differentiation. This is also consistent with former pharmacodynamic trials. Age-adapted reference ranges could improve ABT results.
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PMID:Patient age is a strong independent predictor of 13C-aminopyrine breath test results: a comparative study with histology, duplex-Doppler and a laboratory index in patients with chronic hepatitis C virus infection. 1662 Feb 91

Hepatocyte transplantation is a promising method for supporting hepatic function in a broad spectrum of liver diseases. The aim of this work was to test the efficacy of human fetal liver cells to support the chronic failing liver in an experimental model of carbon tetrachloride (CCl4)-induced cirrhosis in rats. Liver cirrhosis was induced by intraperitoneal administration of CCl4 at a dose of 0.2 ml (50% v/v solution)/100 g body weight, twice a week for 3 months in rats. Ten days after stopping CCl4 administration (experimental day 0), rats received intrasplenic injection of cryopreserved fetal liver cells (FLC, 1 x 10(7) cells in 0.3 ml medium). As a cirrhotic control group, CCl4-induced cirrhotic rats were used with intrasplenic injection of an equal volume of medium alone. Animals were sacrificed on experimental day 15. Human fetal liver cell transplantation almost completely prevented the death of cirrhotic animals during the 2 weeks after treatment, while high ongoing mortality was seen in the cirrhotic control group. Cell transplantation into the spleen normalized total bilirubin and TBARSs levels and increased albumin levels in blood serum, as well as restoring mitochondrial function and liver detoxification function (assessed by cytochrome P450 contents and activity) compared with the activities seen in the cirrhosis control group. In parallel with this restoration of biochemical and functional liver indices, morphological patterns of liver recovery or regeneration after liver cell transplantation were demonstrated in day 15 samples by light microscopy. These were absent in the group that had received only medium alone.
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PMID:Cryopreserved fetal liver cell transplants support the chronic failing liver in rats with CCl4-induced cirrhosis. 1670 Mar 27

1. Liver fibrosis is the compensatory state of cirrhosis. In the long asymptomatic period, it is imperative to select a proper dosing regimen for drugs that are applicable to hepatic fibrosis. Otherwise, progressive deterioration to uncompensated cirrhosis may occur. The present study explored the characteristics of drug metabolism in fibrotic liver. 2. A rat precision-cut fibrotic liver slice (PCFLS) technique was established and the metabolism of verapamil was studied employing this technique. A rat hepatic fibrosis model was successfully induced integrating complex factors that included a high-fat diet, alcohol and CCl4. The PCFLS were incubated under different conditions and lactate dehydrogenase leakage, glutathione S-transferase activity and 3[4,5-dimethythiazole-2-yl]-2,5-diphenyltetrazolium bromide reduction were used as indices to assess PCFLS viability. Activities of phase I and phase II metabolizing enzymes were monitored following treatment with cytochrome P450 (CYP) inducers. Normal and fibrotic liver slices were incubated individually with 10 micromol/L verapamil. The concentration of verapamil in the medium was determined by high-performance liquid chromatography and intrinsic clearance (Cl(int)) was calculated on the basis of the concentration-time curve. 3. The results showed that the PCFLS viability remained steady throughout the 6 h of culture when the thickness of slices was 300 microm and pH of the medium was 7.0; CYP inducers (phenobarbital and ethanol) enhanced CYP2E1, CYP3A1/2 and uridine diphosphate-glucuronate transferase (UDPGT) activities, respectively, in a time-dependent manner. The Cl(int) (microL/min per mg) values differed significantly between normal (9.7 +/- 1.8) and fibrotic (5.6 +/- 1.4) liver slices (P < 0.01). 4. These results suggested that the PCFLS could remain viable for 2-6 h under appropriate conditions. The stability and inducibility of drug-metabolizing enzymes of PCFLS were also demonstrated. Furthermore, the metabolic rate of verapamil in PCFLS was decreased. These findings add further support to the use of PCFLS as a tool to study drug metabolism and to guide clinical medication.
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PMID:Establishment of rat precision-cut fibrotic liver slice technique and its application in verapamil metabolism. 1743 8

1. Liver fibrosis is the compensatory state of cirrhosis. In the long asymptomatic period, it is imperative to select a proper dosing regimen for drugs that are applicable to hepatic fibrosis owing to altered pharmacokinetics and bioavailability. The present study was designed to observe the changes in verapamil pharmacokinetics in rats with early liver fibrosis with respect to alterations in cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). 2. A rat liver fibrosis model was successfully established using several inducers, including a high-fat diet, alcohol and carbon tetrachloride. After rats received a single intravenous or oral dose of verapamil (5 mg/kg), the plasma concentrations of verapamil were determined at scheduled time-points using HPLC. The activity of hepatic and small intestinal microsomal erythromycin N-demethylase (a marker for CYP3A) and the expression of small intestinal cyp3a and multidrug resistance (mdr) mRNA were compared between normal rats and rats with liver fibrosis. 3. The results showed that when verapamil was administered intravenously, the area under the curve (AUC), elimination half-life (T((1/2)(K10))) and mean residence time (MRT) increased significantly, whereas clearance (Cl) decreased, in rats with liver fibrosis compared with normal rats. After oral administration of verapamil, the AUC, (T((1/2)(K10))) and maximum concentration (C(max)) increased, Cl decreased and the absorption half-life (T((1/2)(K01))) and time to peak concentration (T(max)) were unchanged compared with normal rats. The oral bioavailability of verapamil was 32.9% in normal rats and 34.4% in rats with liver fibrosis. Furthermore, decreased CYP3A activity in the liver was accompanied by upregulated cyp3a9/18 and unchanged mdr mRNA in the small intestine compared with normal rats. Expression of cyp3a9/18 and mdr mRNA in the intestine was significantly inhibited by verapamil. 4. The results suggest that the lowered Cl and increased AUC of verapamil after intravenous and oral administration in rats with liver fibrosis were due to downregulation of CYP3A in the liver. The absorption rate of verapamil in rats with liver fibrosis was unchanged because mdr was unchanged and cyp3a was inhibited in the intestine by verapamil itself. There was no notable difference in oral bioavailability between normal rats and rats with liver fibrosis.
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PMID:Effects of liver fibrosis on verapamil pharmacokinetics in rats. 1797 28

Many drugs, including most antiarrhythmics (some of which are now of limited clinical use) are eliminated by the hepatic route. If liver function is impaired, it can be anticipated that hepatic clearance will be delayed, which can lead to more pronounced drug accumulation with multiple dosing. Consequently, the potential risks of adverse events could be increased, especially as antiarrhythmics have a narrow therapeutic index. The present review summarises the available pharmacokinetic data on the most popular antiarrhythmic drugs to identify the enzymes involved in the metabolism of the various agents and confirm whether liver disease affects their elimination. Despite long usage of some of these drugs (e.g. amiodarone, diltiazem, disopyramide, procainamide and quinidine), surprisingly few data are available in patients with liver disease, making it difficult to give recommendations for dosage adjustment. In contrast, for carvedilol, lidocaine (lignocaine), propafenone and verapamil, sufficient clinical studies have been performed. For these drugs, a marked decrease in systemic and/or oral clearance and significant prolongation of the elimination half-life have been documented, which should be counteracted by a 2- to 3-fold reduction of the dosage in patients with moderate to severe liver cirrhosis. For sotalol, disopyramide and procainamide, renal clearance contributes considerably to overall elimination, suggesting that dosage reductions are probably unnecessary in patients with liver disease as long as renal function is normal. The hepatically eliminated antiarrhythmics are metabolised mainly by different cytochrome P450 (CYP) isoenzymes (e.g. CYP3A4, CYP1A2, CYP2C9, CYP2D6) and partly also by conjugations. As the extent of impairment in clearance is in the same range for all of these agents, it could be assumed that they have a common vulnerability and that, consequently, hepatic dysfunction will affect CYP-mediated phase I pathways in a similar fashion. The severity of liver disease has been estimated clinically by the validated Pugh score, and functionally by calculation of the clearance of probe drugs (e.g. antipyrine). Both approaches can be helpful in estimating/predicting impairments in drug metabolism, including antiarrhythmics. In conclusion, hepatic impairment decreases the elimination of many antiarrhythmics to such an extent that dosage reductions are highly recommended in such populations, especially in patients with cirrhosis.
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PMID:Antiarrhythmics: elimination and dosage considerations in hepatic impairment. 1802 86


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