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)

To determine the course of hepatic recovery from subchronic oral administration of carbon tetrachloride (CCl4), male F-344 rats were gavaged with 0, 20, or 40 mg CCl4/kg, 5 days/week, for 12 weeks. Exposure to CCl4 caused dosage-dependent increases in relative liver weight and the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, and cholesterol as well as a dosage-dependent decrease in hepatic cytochrome P450. Centrilobular hepatocellular vacuolar degeneration, necrosis, and cirrhosis occurred at both 20 and 40 mg/kg, with dosage-dependent severity. Reversibility of these reported effects varied with parameter. By Day 8 postexposure, necrosis had disappeared and all serum indicators and cytochrome P450 had returned to control levels. By Day 15 postexposure, the severity of the vacuolar degeneration had decreased. Reversibility of cirrhosis was dosage dependent; complete recovery occurred in the low- but not the high-dose group by Day 15. The disappearance of the increase in relative liver weight was also dependent on dosage; the low- but not the high-dose group had returned to the control level by Day 22. In an attempt to measure persistent hepatic damage, liver uptake relative to the spleen was determined for a sulfur colloid labeled with technetium-99m and for tritiated 2-deoxyglucose. Neither method consistently measured hepatic damage in cirrhotic livers due, in part, to the high degree of variability in the tracer uptake data.
 ...
PMID:Assessment of hepatic indicators of subchronic carbon tetrachloride injury and recovery in rats. 225 19

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

Partial hepatectomy in male adult rats results in raised serum estrogen levels and demasculinization of certain aspects of hepatic metabolism. Some constitutive forms of hepatic cytochrome P450 are sex-dependent and we have previously demonstrated demasculinization of cytochrome P450 isozyme distribution in a rat model of cirrhosis. As liver regeneration is an integral component of cirrhosis, the present study was performed to ascertain the effects of regeneration on hepatic cytochrome P450 isozyme composition and serum sex steroid concentrations. Adult male rats were subjected to 65% partial hepatectomy or sham-operation. The position-specific hydroxylation of androstenedione was used as a probe for isozyme activity. Serum sex steroids, hepatic enzymes, and hepatic deoxyribonucleic acid synthesis were measured in groups of animals at 0, 6, 24, 48, and 72 h. By 72 h total microsomal cytochrome P450 in partially hepatectomized animals had fallen to 66% of that in nonoperated animals. In both partially hepatectomized and sham-operated animals, androstenedione 7 alpha- and 16 beta-hydroxylase activity returned to preoperative levels by 48 h. However, the male-specific androstenedione 16 alpha- and 6 beta-hydroxylase activities and aromatase activity remained suppressed in partially hepatectomized liver. Serum estradiol increased eightfold in partially hepatectomized rats and peaked at 6 h followed by a gradual fall to control values. No change in serum estradiol was observed in sham-operated animals. We conclude that demasculinization of hepatic oxidative metabolism occurs in regenerating rat liver. The early rise in serum estradiol is consistent with a role for this hormone in the changes in cytochrome P450 observed, and possibly the process of liver regeneration.
 ...
PMID:Effect of liver regeneration on hepatic cytochrome P450 isozymes and serum sex steroids in the male rat. 291 47

Drug-induced injury to the liver can mimic any form of acute or chronic liver disease. Acute injury to the liver frequently is due to the action of cytochrome P450, which breaks down drugs into electrophiles or free radicals; these reactive metabolites can covalently bind to protein and unsaturated fatty acids or induce lipid peroxidation, respectively. These events may impair vital functions of the cell, such as maintenance of calcium homeostasis, leading to death; or hypothetically they may elicit a hypersensitivity reaction directed mainly at the liver. Glutathione and tocopherol play critical roles in cellular defense. Cholestatic disease caused by drugs results from a selective disturbance in bile secretion. Agents such as estrogens, chlorpromazine, and monohydroxy bile acids alter the chemical and physical properties of membranes, leading to impaired activity of carriers and pumps for bile acids and electrolytes. Certain drugs produce chronic liver disease that is pathologically identical to chronic active hepatitis, biliary cirrhosis, or alcoholic liver disease.
 ...
PMID:Drug-induced hepatotoxicity. 351 64

Hydroxylase and demethylase activity of cytochrome P450-dependent liver monooxygenases was estimated in healthy persons and patients with chronic diseases of the hepatobiliary system. Metabolite urine content and 4-hydroxyantipyrine and norantipyrine clearance were measured within 24 h after oral antipyrine administration (10 mg/kg). It was shown that progressive antipyrine metabolic derangements depended on the form and stage of chronic diffuse liver lesion, which was especially marked in patients with chronic active viral hepatitis, liver cirrhosis with or without ascites and with signs of encephalopathy. More considerable inhibition of N-demethylase monooxygenase activity as compared to hydroxylase activity in patients with chronic active viral hepatitis showed different sensitivity of some cytochrome P450 forms to pathogenetic factors. It could be of diagnostic value. The authors put forward the idea of interaction between the oxygenase and immune systems in drug detoxication in liver diseases.
 ...
PMID:[Monooxigenase activity in liver diseases (study based on data of antipyrine metabolism)]. 357 85

Hepatic cirrhosis produced by repeated inhalation of carbon tetrachloride is associated with reduced levels of microsomal cytochrome P450. In this study the C19-steroids androstenedione and testosterone were used as specific probes of the functional activity of several forms of cytochrome P450 in microsomal fractions from control and cirrhotic rat liver. The principal finding, that androstenedione 16 alpha-hydroxylation and testosterone 2 alpha-, 16 alpha-, and 17 alpha-hydroxylation were reduced to 14%-38% of control activity, strongly suggests that levels of the male sexually differentiated cytochrome P450 (P(450)16 alpha) are decreased in hepatic cirrhosis. The activity of other cytochrome P450-mediated C19-steroid hydroxylases, with the exception of androstenedione 6 beta-hydroxylase, appeared essentially unaltered in microsomes from cirrhotic rats. Cirrhosis induced by carbon tetrachloride was also associated with greatly decreased activity of the microsomal cytochrome P450-independent 17 beta-oxidoreductase, an enzyme that catalyzes the conversion of androstenedione to testosterone. Consequently, and in view of the impaired activity of cytochrome P450-mediated testosterone 17 alpha-hydroxylation, the capacity of cirrhotic microsomes to catalyze the interconversion of androstenedione and testosterone was much lower than that of control microsomes. The present data confirm and extend earlier observations that selective impairment of drug oxidation pathways occurs in hepatic cirrhosis. These changes are unrelated to the acute toxicity produced by carbon tetrachloride exposure. The available evidence supports the assertion that specific forms of cytochrome P450 are subject to altered regulation in cirrhosis.
 ...
PMID:Impaired androgen 16 alpha-hydroxylation in hepatic microsomes from carbon tetrachloride-cirrhotic male rats. 358 1

The intact cell hypothesis states that a reduced number of intrinsically normal hepatocytes, together with hemodynamic alterations, explains decreased drug metabolism in cirrhosis. We explored this hypothesis by comparing results of the aminopyrine breath test with in vitro measurements of aminopyrine N-demethylation and morphometrically determined liver cell volume in a rat model of cirrhosis. Aminopyrine N-demethylation in vivo (ABT-k) was 0.98 +/- 0.10/h (mean +/- SD) in controls. The cirrhotic rats were separated into those with normal (NCR) and those with abnormal ABT-k (PCR). Microsomal aminopyrine N-demethylase averaged 2.08 +/- 0.77 and 2.09 +/- 0.54 mumol/min in controls and NCRs, respectively; it was reduced to 1.00 +/- 0.81 mumol/min (p less than 0.02) in PCRs. Morphometrically determined hepatocellular volume was 18.8 +/- 2.8, 17.1 +/- 1.9, and 11.6 +/- 6.1 ml in controls, NCRs, and PCRs, respectively, PCRs being lower than controls (p less than 0.01) and NCRs (p less than 0.05). When N-demethylase and cytochrome P450 were related to hepatocellular volume (in milliliters), no significant difference between the three groups was apparent. We conclude that reduced aminopyrine N-demethylation in progressed cirrhosis is mainly due to a loss of liver cell volume. The function per liver cell volume remains constant, however, thus favoring the intact cell hypothesis for the handling of slowly metabolized compounds such as aminopyrine.
 ...
PMID:Aminopyrine N-demethylation by rats with liver cirrhosis. Evidence for the intact cell hypothesis. A morphometric-functional study. 362 18

Abuse of alcohol (ethanol) and abuse of an increasing number of drugs (e.g. analgesics and sedatives) are among the outstanding social and medical problems of many industrialized countries including Switzerland. Since alcohol consumption has profound effects on both the pharmacokinetic and pharmacodynamic actions of a variety of drugs, the rational use of drugs in alcoholics is an increasingly difficult task and requires a thorough understanding of the physiologic, biochemical, pharmacologic and toxic actions of alcohol. Clinically the most important targets of alcohol action are the liver and the central nervous system (CNS), both of which are frequently involved in the mediation of potentially fatal interactions between drugs and alcohol. In practice the most important of these interactions include (a) inhibition of hepatic (cytochrome P450 dependent) drug oxidation by acute alcohol ingestion resulting in increased bioavailability of drugs that are predominantly excreted by hepatic metabolism, (b) inhibition of acetaldehydedehydrogenase by some drugs with production of an acute flushing reaction to alcohol, (c) increased sensitivity of the CNS to a variety of sedative drugs following acute alcohol ingestion leading to enhanced CNS toxicity of most psychoactive drugs, (d) stimulation of hepatic drug oxidation and decreased CNS sensitivity to sedatives after chronic alcohol abuse, thus explaining the "metabolic" and pharmacodynamic tolerance of these patients towards psychoactive agents, and (e) depressed drug metabolism and increased CNS sensitivity to sedative and hypnotic drugs in patients with cirrhosis of the liver. The mechanisms and practical consequences of the clinically most important influences of acute and chronic alcohol ingestion on the pharmacokinetics and the pharmacodynamic actions of drugs are outlined.
 ...
PMID:[Alcohol, alcoholism and drugs]. 391 83

Cytochrome P450 levels are often low in the cirrhotic liver but the reason for this has not been established. Because changes in heme metabolism may reduce hepatic levels of cytochrome P450, the relationship of heme turnover to cytochrome P450 levels has been examined in rats with cirrhosis. Cirrhosis was produced by repeated carbon tetrachloride inhalation. In animals with cirrhosis, hepatic microsomal cytochrome P450 content was significantly less (32%) than in controls. Heme synthesis was assessed by measuring the activity of mitochondrial delta-amino-levulinic acid synthetase and also by determining the incorporation (within 30 min) of radiolabeled delta-aminolevulinic acid into the microsomal heme fraction. Both these parameters were normal in rats with CCl4-induced cirrhosis. In addition, the activity of microsomal heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin, was not altered. Cytochrome P450 heme degradation was then determined directly by injecting radiolabeled delta-aminolevulinic acid and measuring radioactivity in CO-binding particles (microsomes incubated with protease to remove cytochrome b5) prepared at various times thereafter. By this method, the degradation rate of cytochrome P450 heme did not differ between rats with cirrhosis and controls. Finally, the availability of hepatic heme for formation of hemoproteins was deemed to be satisfactory in cirrhotic liver because tryptophan pyrrolase saturation was comparable with controls, and also because heme administered in vivo did not enhance hepatic clearance of the cytochrome P450 substrate antipyrine. The failure to find defective heme biosynthesis or accelerated heme breakdown and the evidence that heme is available in amounts that do not restrict hemoprotein formation indicate that aberrant heme metabolism is not the cause of low cytochrome P450 levels in this rat model of cirrhosis.
 ...
PMID:Hepatic heme metabolism and cytochrome P450 in cirrhotic rat liver. 400 1

The authors have studied the action of fluorine, administered by inhalation, on the liver metabolism of a chemical carcinogen: dimethylnitrosamine (DMN). The results demonstrate a decrease in the level of cytochrome P450 and in the activity of benzo(a)pyrene hydroxylase in animals treated with DMN or DMN + HF. The greater inhibition in the presence of HF is paralleled by a decrease in the weight of the liver and in the synthesis of liver microsomal proteins. This reduction of activity (with the exception of dimethylnitrosamine demethylase which is unaffected) is supported by the result of the histological examinations showing two different types of lesion-necrotic toxic hepatitis and post-hepatitic cirrhosis - the frequency of which is much higher in the presence of fluorine.
 ...
PMID:[Effect of HF on the hepatic metabolism of dimethylnitrosamine in the rat]. 667 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>