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

The microsomal content and activity of the principal male-specific cytochrome P450 2C11 are reduced in cirrhotic rat liver. In order to define the pathophysiological mechanism for such changes, the present study was undertaken to determine the time course of impaired P450 2C11 expression in relation to the development of cirrhosis during intake of a choline-deficient diet. Fatty infiltration of the liver was evident after 6 weeks of intake but hepatic fibrosis was not present until 10 weeks, when fine fibrotic bands in a perisinusoidal distribution were observed. Fibrotic bands were progressively more prominent at 20 and 25 weeks and cirrhosis was established by 30 weeks of dietary intake. Portal pressure, as measured by saline manometry and indicated by splenomegaly, appeared to increase gradually after 6 weeks and by 25 weeks values were significantly greater than controls. The microsomal content of P450 2C11 and its associated steroid 16 alpha-hydroxylase activity were unchanged at 6 weeks but were decreased to around 30% of control from 10 weeks of intake of the choline-deficient diet to the end of the experimental period (30 weeks). Serum bile acids were approximately 2-fold greater in choline-deficient rats from 10 weeks. Similarly, serum estradiol concentrations were elevated (to 2.5-fold of control) in male rats after 10 weeks intake of the choline-deficient diet; this increase was sustained in 30-week cirrhotic rats. On the other hand, there was no evidence of altered serum testosterone until 30 weeks of dietary deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis. 156 Mar 81

The metabolism of lidocaine to its major metabolite monoethylglycinexylidide (MEGX) was studied in human liver microsomes of 13 kidney transplant donors and of one patient with liver cirrhosis. Interindividual variation in metabolite formation was considerable. Biphasic kinetics indicated the involvement of at least two distinct enzymatic activities. With use of a series of antisera that recognize different human cytochrome P450 isozymes, we were able to identify an enzyme of the P450III gene family as one of two enzymes. By expressing human P450IIIA4 complementary deoxyribonucleic acid (cDNA) in HepG2 cells, we directly demonstrated lidocaine-deethylase activity for this P450 isozyme. These data suggest that P450IIIA4 is at least in part responsible for microsomal MEGX formation.
 ...
PMID:Lidocaine metabolism in human liver microsomes by cytochrome P450IIIA4. 258 9

Oral load with 200 mg Lidocain was performed in 370 patients with chronic liver disease. The 120- and 240-minute Lidocain plasma concentrations as well as the 30- and 60-minute MEGX plasma concentrations, main metabolite of Lidocain, were measured by means of gas chromatography and with the commercial TDX test from the firm Abbott. No side effects caused by the load were observed and all of the patients resorbed Lidocain. Peak concentrations were found both for Lidocain and for MEGX in the 60-minute tests. Patients with liver cirrhosis of different aetiology showed significantly higher Lidocain plasma concentrations and lower MEGX values than patients with chronic non-cirrhotic liver disease. The differentiation of these two groups of patients was most successful via the determination of the 240-minute Lidocain plasma concentration. Oral load with 200 mg Lidocain has turned out to be a practicable and meaningful test for the estimation of the Cytochrom P450-dependent liver function.
 ...
PMID:[Lidocaine elimination and MEGX formation after oral lidocaine administration--a practicable test for assessment of quantitative liver function]. 748 15

We have recently reported that disease-specific differential alterations in the hepatic expression of xenobiotic-metabolizing cytochrome P450 (CYP P450) enzymes occur in patients with advanced liver disease. In order to determine whether the observed changes in CYP proteins are modulated at pre- or post-translational levels, we have now examined the hepatic levels of mRNA for CYPs 1A2, 2C9, 2E1 and 3A4 by solution hybridization in the same livers of 20 controls (surgical waste from histologically normal livers), 32 cases of hepatocellular and 18 of cholestatic severe chronic liver disease. CYP1A2 mRNA and CYP1A immunoreactive protein were both reduced in livers with hepatocellular and cholestatic types of cirrhosis. In contrast, CYP3A4 mRNA and protein were reduced only in livers from patients with hepatocellular diseases. For 1A2 and 3A4 there were significant correlations between mRNA species and the respective protein contents (rS1A2 = 0.74, rS3A4 = 0.64, P < 0.0001). CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of liver disease, but 2C protein was reduced only in patients with cholestatic dysfunction. The correlation between CYP2C9 mRNA and protein, was also significant (rs = 0.36, P < 0.005) but mRNA levels accounted for only 13% of the variability in protein rankings. This is probably a consequence of other CYP2C proteins apart from 2C9 being detected by the anti-2C antibody. CYP2E1 mRNA and protein were reduced in patients with cholestatic liver disease, but in hepatocellular disease the expression of only CYP2E1 mRNA was decreased. CYP2E1 mRNA was significantly correlated with CYP2E1 protein but accounted for only 18% of the variability in protein rankings (rs = 0.43, P < 0.0005). Taken collectively these data indicate that the disease-specific alterations of xenobiotic-metabolizing CYP enzymes among patients with cirrhosis is due, at least in part, to pre-translational mechanisms. The lack of a strong correlation between CYP2E1 mRNA and protein suggests that this gene, like its rat orthologue, may be subject to pre-translational as well as translational and/or post-translational regulation.
 ...
PMID:Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. 774 59

Low-molecular hydrocarbons (butan, pentan) from the exhaled air as lipid peroxidation (LPO) markers were quantified in patients with chronic diffuse liver diseases. The study was also made of microsomal oxidation enzymic activity by antipirin metabolism. The above parameters were followed up in the course of antioxidant treatment. As shown by total butan and pentan levels, LPO activity varied with the disease, being high in hepatic cirrhosis and primary biliary cirrhosis, but low in chronic active hepatitis and fat dystrophy. Increased levels of butan and pentan occurred in association with inhibited activity of P450-dependent monooxygenases. This was determined by antipirin biotransformation and confirmed by a strong inverse correlation between the amount of hydrocarbons and antipirin metabolites (4-hydroxy- and norantipirin) clearance. In the course of antioxidant therapy the most pronounced inhibiting action on formation of low-molecular hydrocarbons was distinctive of essenciale, pikamilon and copmplivit. Relevant efficacy of carsil was weaker. Similar regularity for these drugs takes place in relation to activation of microsomal oxidation.
 ...
PMID:[Lipid peroxidation markers in the exhaled breath and microsomal oxidation in patients with chronic diffuse liver diseases]. 778 77

To determine whether cytochrome P450 proteins were differentially altered in severe chronic liver diseases, we examined 50 livers removed at liver transplantation from patients with end-stage cirrhosis, including 18 with and 32 without cholestasis, and compared the results with 21 histologically normal livers. NADPH-cytochrome c reductase activities were unaltered in microsomes from cirrhotic livers. Total cytochrome P450 content was significantly reduced. The catalytic activities of four xenobiotic-metabolizing P450s and the level of the corresponding proteins were differentially altered. Thus, P450 3A-supported testosterone 6 beta-hydroxylase activity and 3A protein appeared to be reduced, but only in the subgroup without cholestasis was this change significant. In contrast, 2E1 and the related N,N-dimethylnitrosamine N-demethylase activity were clearly reduced in livers from patients with cholestatic forms of cirrhosis but appeared not to be changed in other cirrhotic livers. Similarly, P450 2C protein was reduced only in patients with severe chronic cholestasis. Finally, P450 1A2 and 1A2-supported ethoxyresorufin O-deethylase activity were significantly reduced in hepatic microsomes from patients with both types of advanced liver disease. In summary, these data demonstrate that cytochrome P450 proteins are selectively altered in severe chronic liver disease, some being profoundly decreased, others less so or not at all. Our results also suggest that there may be different patterns of altered hepatic P450 expression according to the presence or absence of cholestasis in patients with cirrhosis severe enough to require transplantation.
 ...
PMID:Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. 780 44

Although it is frequently stated that patients with cirrhosis are more sensitive to benzodiazepines, the relative roles of impaired elimination and altered responsiveness have not been clarified. We evaluated the pharmacokinetics, pharmacodynamics, and sensitivity to triazolam in six patients with clinically stable cirrhosis and six age-matched control subjects. Our findings show that there were no significant differences between the patients with cirrhosis and the control subjects in any of the pharmacokinetic parameters. Drug effect, measured as postural sway, was also similar in the patients with cirrhosis and control subjects; therefore the ratio of effect area under the curve to concentration area under the curve, a measure of sensitivity, did not differ significantly between the patients with cirrhosis and the control subjects. Because triazolam is metabolized by P4503A, we hypothesized that the effects of cirrhosis on drug metabolism may differ with respect to the specific P450 responsible for the oxidation of this drug. These effects may differ because of the relative sparing of a specific P450 and because of an extrahepatic site of metabolism.
 ...
PMID:Triazolam in cirrhosis: pharmacokinetics and pharmacodynamics. 827 18

The metabolism of antipyrine to each of its three major metabolites 4-hydroxy-, 3-methylhydroxy- and norantipyrine has previously been demonstrated to be differentially affected in alcoholic cirrhosis. This study compared the metabolism of antipyrine to its metabolites in 30 patients with alcoholic cirrhosis to 15 patients with non-alcoholic cirrhosis and 20 healthy controls. Both groups of cirrhotic patients were comparable with respect to their disease stage, as assessed by the Child-Pugh classification. Compared to controls, patients with alcoholic and non-alcoholic cirrhosis showed a comparable significant reduction in antipyrine clearance and increase in antipyrine half-life. The reduction in antipyrine clearance was due to a reduction in the formation rate of all three antipyrine metabolites in both alcoholic and non-alcoholic cirrhotics. In both groups, the formation rate of norantipyrine was reduced to a greater extent than of 3-methylhydroxy- and 4-hydroxyantipyrine. No significant differences in the parameters of antipyrine elimination, however, were observed between patients with alcoholic and non-alcoholic cirrhosis. Parameters of antipyrine elimination correlated significantly to the Child-Pugh score and single laboratory parameters, however, the correlation coefficients were generally low (< 0.56). The present results suggest that the P450 enzymes involved in antipyrine metabolism are differentially affected in cirrhosis, but there appear to be no differences in the activity of the enzymes between alcoholic and non-alcoholic cirrhosis. Antipyrine metabolism, therefore, depends on the severity rather than the etiology of liver disease and may serve as a measure of hepatic function irrespective of the cause of liver disease.
 ...
PMID:Antipyrine elimination in patients with alcoholic and non-alcoholic cirrhosis. 844 50

Genetic polymorphisms of various cytochromes P450 have recently been described and could be implicated in the individual susceptibility of alcoholics to ethanol-related diseases. Rsal and Dral polymorphisms of CYP2E1 and Mspl polymorphism of CYP1A1 were studied in 260 controls and 511 alcoholic patients, without any clinical symptoms (n = 202) or with various ethanol-related diseases (n = 309), such as liver cirrhosis (n = 110), esophageal cancer (n = 62), upper aerodigestive tract cancer (n = 96), and other miscellaneous diseases (n = 41). Frequencies of the mutated alleles were found to be 2.5% (Rsal), 7.9% (Dral), and 8.7% (Mspl) in controls; 4%, 14.1%, and 12% in alcoholics without clinical symptoms; and 3.1%, 12.5%, and 11.2% in alcoholics with ethanol-related diseases. The only significant difference was found in the Dral polymorphism, whose frequency was enhanced in alcoholics with (p < 0.05) or without ethanol-related diseases (p < 0.01) when compared with controls. No differences were found between alcoholics without clinical symptoms and alcoholics with cirrhosis, esophageal cancer, or upper aerodigestive tract cancer. However, in liver cirrhosis and in ethanol-related cancers, the rare Dral-C allele was three times less frequent in patients under the age of 45 than in older patients, suggesting a protective role for this allele. In conclusion, our data indicate that the aforementioned mutations do not play a critical role in the development of cirrhosis, esophageal cancer, or upper aerodigestive tract cancers in Caucasians.
 ...
PMID:Cytochromes P4502E1 and P4501A1 genotypes and susceptibility to cirrhosis or upper aerodigestive tract cancer in alcoholic caucasians. 889 24

Amprenavir (141W94) is extensively metabolized by P450 cytochromes, specifically, CYP3A4. Because hepatic insufficiency reduces P450-mediated metabolism, the concentrations in plasma of drugs metabolized through this pathway are often increased in subjects with liver disease. Following administration of a single, oral dose of 600 mg of amprenavir, pharmacokinetic parameters were determined for 10 subjects with severe cirrhosis, 10 subjects with moderate cirrhosis, and 10 healthy volunteers. Model-independent methods for determining the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC(0-infinity)) showed an increase in amprenavir AUC(0-infinity) of 2.5-fold in the group with moderate cirrhosis and 4.5-fold in the group with severe cirrhosis compared with that in the control group of healthy volunteers (P < 0.05). AUC(0-infinity) was linearly related to the severity of liver disease, as assessed by the Child-Pugh score. Of the laboratory data used to calculate the Child-Pugh score, only the mean total bilirubin concentration showed a significant relationship with AUC(0-infinity). The relationship between the total bilirubin concentration and the AUC(0-infinity) of amprenavir was well characterized by a simple E(max) model, suggesting that the total bilirubin concentration may be a useful parameter for predicting the amprenavir AUC in subjects with hepatic insufficiency. Finally, the sera of cirrhotic subjects showed significant decreases in the levels of alpha(1)-acid glycoprotein, the primary plasma binding protein for amprenavir. On the basis of the results of this study, for an exposure equivalent to a clinical dose of 1,200 mg twice daily in subjects without cirrhosis, subjects with Child-Pugh scores of 5 to 8 should receive a twice-daily 450-mg dose of amprenavir, and subjects with Child-Pugh scores of 9 to 15 should receive a twice-daily 300-mg dose of amprenavir.
 ...
PMID:Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function. 1072 76


1 2 3 Next >>