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)

Cirrhosis was induced in Wistar-Kyoto rats by intragastric administration of carbon tetrachloride. Microsomes were obtained from the renal cortex and outer medulla and incubated with [14C]arachidonic acid (AA) (0.2-0.4 microCi) in the presence or absence of indomethacin, NADPH, and SKF-525A. Cytochrome P-450-dependent AA metabolites (those whose formation required NADPH, were inhibited by SKF-525A, but not by indomethacin) were separated by thin-layer chromatography and high-pressure liquid chromatography (HPLC). Compared to controls, total synthesis of cytochrome P-450-dependent AA metabolites was reduced in cirrhotic rats (renal cortex: cirrhotics 380 +/- 52 vs. controls 493 +/- 68 pg/mg protein per 30 min; p less than 0.05; renal outer medulla: cirrhotics 304 +/- 57 vs. controls 387 +/- 53 pg/mg protein per 30 min; p less than 0.05). The cytochrome P-450-dependent AA metabolites were composed of three peaks separated by HPLC. Peak I, which had a retention time of 16.3 +/- 0.3 min and comigrated with 11,12-dihydroxyeicosatrienoic acid, and peak II, which had a retention time of 18.7 +/- 0.4 min and comigrated with 19- and 20-hydroxyeicosatetraenoic acid, were not different in cirrhotics and controls. Peak III, which had a retention time of 26.8 +/- 0.3 min, and comigrated with 11,12-epoxyeicosatrienoic acid, was significantly decreased in the renal cortex of cirrhotic rats compared to controls (cirrhotics 316 +/- 40 vs. controls 473 +/- 89 pg/mg protein per 30 min; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal cytochrome P-450-dependent metabolism of arachidonic acid in cirrhotic rats. 190 94

To test further the competence of the cirrhotic liver to metabolize xenobiotics, hepatocytes were isolated from control and CCl4-induced cirrhotic male or female rats. Histologically micronodular cirrhosis was present in all CCl4-treated rats, while control rats had normal livers. Portal perfusion pressure and intrahepatic collagen content were also significantly increased by CCl4 administration. In male rats, no significant differences in levels of circulating transaminases nor in alkaline phosphatase was observed between cirrhotic and control rats, while CCl4-treated females had slightly higher than normal serum transaminase levels at the time of the studies. Hepatocytic cytochrome P-450 and basal xenobiotic biotransformation were unaffected by micronodular cirrhosis in both genders; calculation of the aminopyrine and 7-ethoxycoumarin intrinsic clearances (Cli) revealed, however, a slightly decreased transformation potential in hepatocytes obtained from cirrhotic females, a phenomenon not observed in cirrhotic male rats. It is speculated that the observed reduction in Cli may have been independent of cirrhosis per se, owing to the perduring cytotoxic effect of CCl4 as evidenced by the higher than normal level of transaminases in female rats. Finally, male rats were subjected to in vivo administration of phenobarbital or 3-methylcholanthrene; both compounds led to significant induction of the mixed-function oxidase system, which was similar in magnitude and in selectivity in control and cirrhotic rats as illustrated by calculation of the Michaelis-Menten kinetic parameters for aniline p-hydroxylation, aminopyrine-N-demethylation, 7-ethoxycoumarin-O-deethylation, and p-nitrophenol UDP-glucuronyl transferase. We conclude that in well-established but compensated and hepatolysis-free micronodular cirrhosis, hepatocytes are fully able to transform xenobiotics and to respond normally and selectively to inducers of drug metabolism.
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PMID:Unimpaired induction of drug-metabolizing enzymes in hepatocytes isolated from rats with micronodular cirrhosis. 205 6

Female Uje: WIST rats received thioacetamide (TAA) in the tap water (0.3 g/l) from the 4th to 6th months of life to produce experimental liver cirrhosis. Immediately, 2 and 7 days after TAA cessation it was investigated by means of in vivo (caffeine and metamizol elimination) and vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation), whether this animal model represents the restricted cytochrome P-450-dependent biotransformation comparable to human liver cirrhosis. The total capacity of the liver was diminished immediately and 2 days after TAA cessation. After 7 days the capacity was unchanged compared to the controls or partly even enhanced. Therefore, this animal model reflects rather a short time than a stable alteration of biotransformation after TAA cessation comparable to human liver cirrhosis.
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PMID:[Effect of 3 months of thioacetamide treatment on liver biotransformation in vivo and in vitro (various times after discontinuation)]. 209 75

In female Uje:WIST rats micronodular liver cirrhosis was produced by thioacetamide (TAA) given in the drinking water (0.3 g/l) from the 4th to 6th months of life. 14 d after TAA cessation it was examined, whether this animal model reflects the restricted cytochrome P-450-dependent biotransformation in severe stages of human liver cirrhosis by in vivo (caffeine and metamizol elimination) and in vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation, ethylmorphine N-demethylation). The total biotransformation capacity was unchanged in TAA rats, partly even enhanced. Only several in vitro parameters reflect diminished cytochrome P-450-dependent biotransformation calculated per weight unit comparable to severe stages of human liver cirrhosis. Therefore, the chosen experimental conditions are suitable for conclusions concerning cytochrome P-450-dependent biotransformation in early rather than in severe stages of human liver cirrhosis.
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PMID:Cytochrome P-450-dependent biotransformation in Uje:WIST rats with chronic liver injury induced by thioacetamide. 261 91

A technique of feeding alcohol as part of a liquid diet is reviewed that achieves an alcohol consumption of clinical relevance, while maintaining dietary control and providing adequate nutrition. With this procedure, blood alcohol levels are obtained which mimic clinical conditions and allow experimental duplications of many pathological complications caused by alcohol. In the rat, the liquid diet technique provides a model for the alcoholic fatty liver, various alcohol-induced metabolic, endocrine and central nervous system abnormalities (including tolerance and dependence) and the interaction of ethanol with industrial solvents, many commonly used drugs, analgesics, carcinogens and nutrients. This technique also resulted in the discovery of a new pathway of ethanol metabolism in the microsomes involving an ethanol-specific cytochrome P-450 (P450IIE1), which has now been confirmed in man. P450IIE1 contributes not only to the metabolic tolerance to ethanol, but also explains the enhanced susceptibility of the alcoholic to many ubiquitous xenobiotic agents. The liquid diet technique provides the flexibility to adjust to special experimental or physiological needs by allowing for various substitutions including changes in lipids, proteins or other dietary constituents. This procedure is thereby ideally suited for the study of the interactions of alcohol with deficiency or excess of various nutrients. The technique also facilitates the comparison with controls by simplifying pair feeding procedures. Although the flexibility of the liquid diet technique is one of its key advantages, a standard 'all purpose' liquid diet is described which is appropriate for most experimental applications. In addition, two other general formulae are given, namely a low fat diet (that allows the study of the effects of ethanol in the presence of minimal hepatic lipid accumulation) and a high protein diet (to meet increased needs, e.g. during pregnancy and lactation). The optimal amount of ethanol for the rat liquid diet was found to be 5 g/dl or 36% of total energy. With lesser amounts of alcohol, intake falls below a critical threshold; blood levels of alcohol then become negligible and the model becomes irrelevant to clinical conditions. In the rat, amounts of ethanol above 5 g/dl were not found to be associated with any further gain in alcohol ingestion. By contrast, in the baboon, the ethanol content could be raised profitably to 7 g/dl or 50% of total energy and resulted in the development of cirrhosis. This higher alcohol intake, together with species difference, may explain the greater severity of liver lesions produced by alcohol in the baboon.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Liquid diet technique of ethanol administration: 1989 update. 266 28

Elevated serum estradiol concentrations and specific changes in the biliary excretion of some androstenedione metabolites have been reported in male rats with portal bypass produced by portal vein ligation (PVL). In this study, the hypothesis that male-specific forms of cytochrome P-450 are altered after PVL was tested by measuring microsomal steroid hydroxylase activities. Consistent with earlier findings in the intact animal, androstenedione 16 alpha-hydroxylase activity was reduced after PVL to 44% of control (P less than 0.05). Other pathways of androstenedione hydroxylation, and total estrogen formation (after androstenedione aromatization) were unchanged. Although total estrogen formation was not different, a sevenfold greater proportion of estradiol was produced in PVL rat microsomes. Additional experiments revealed that PVL selectively reduced the rate of microsomal estradiol 16 alpha-hydroxylation (to 56% of control, P less than 0.02). Levels of cytochrome P-450UT-A, the microsomal steroid 16 alpha-hydroxylase, were lower after PVL (56% of control, P less than 0.05), so that the present observations are consistent with the earlier suggestion that portal bypass is associated with the selective downregulation of this enzyme. Since downregulation of cytochrome P-450UT-A also occurs in experimental hepatic cirrhosis, portal hypertension may well contribute significantly to altered drug metabolism in liver disease. Impaired hepatic elimination of androstenedione by hydroxylation may indirectly enhance extrahepatic aromatization of the androgen. The decreased activity of hepatic estradiol 16 alpha-hydroxylation after PVL would enhance the accumulation of estradiol, the biologically more potent estrogen.
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PMID:Downregulation of the male-specific hepatic microsomal steroid 16 alpha-hydroxylase, cytochrome P-450UT-A, in rats with portal bypass. Relevance to estradiol accumulation and impaired drug metabolism in hepatic cirrhosis. 270 29

Immunohistochemical examinations were carried out for the study of cytochrome P-450 implication in the human hepatic disorders. An isozyme of human hepatic P-450 (P-450-HM1) with the m.w. of 51,000 was purified from human autopsied liver. Antibody against P-450-HM1 was prepared in rabbits, of which specificity was confirmed by Western blot. Eighty-three livers (27 autopsies and 56 biopsies, M:F = 63:20), which were either normal or of various hepatic disorders such as acute or chronic hepatitis, cirrhosis and hepatocellular carcinomas, were examined by the method of avidin-biotin-complex technique. It was revealed that immunoreactive hepatocytes were diffused throughout the lobule of the fetal liver. In the normal livers as well as those of acute and chronic hepatitis, positive hepatocytes were found in the centrilobular zone. Three of the 4 cases treated with beta-interferon showed faint staining; and the presence of positive individual hepatocytes was considered to be induced by steroid therapy. In the livers with chronic hepatitis and cirrhosis, hepatocytes near the perifibrous region and those trapped in the portal triad by thin fibrous connective tissue, as well as in the regenerating nodules, were strongly stained, which indicate that P-450-HM1 is expressed in the regenerating hepatocytes. Hepatocellular carcinomas, however, were devoid of immunohistochemistry. From these results, the antibody might be a useful tool for differentiating regenerating nodule from hepatocellular carcinoma.
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PMID:[Clinico-pathological studies of cytochrome P-450 on human hepatic disorders]. 276 18

Implications of P-450 in human hepatic disorders were immunohistochemically examined. We first confirmed that an antibody against P-450-HM1, an isozyme of cytochrome P-450 which was purified from human livers at autopsy, detects only P-450 on immunoblots. In a study of 79 consecutive autopsied livers using the avidin-biotin-peroxidase complex method, the antibody reacted strongly with fetal hepatocytes, the reaction being more intense in the left lobe than in the right lobe. In normal livers, immunoreactivity was confined to centrilobular hepatocytes, decreasing in the periportal zone. Enhanced expression was occasionally found in scattered hepatocytes and in hepatocytes surrounding sublobular veins; this enhancement was related to longterm steroid therapy. No specific induction was observed in patients with toxic hepatitis. In patients with fibrosis, cirrhosis, or regenerative nodules, however, P-450-positive hepatocytes were observed in the periportal and middle zones as well as in the central zone. In contrast, hepatocellular carcinomas were devoid of P-450 immunoreactivity. These results suggest that P-450-HM1, which is abundant in the fetal liver, is reexpressed in regenerating hepatocytes but not in cancers.
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PMID:Distributional variation of P-450 immunoreactive hepatocytes in human liver disorders. 279 57

To verify whether a mild, but prolonged liver injury by chemicals needing bioactivation causes both hepatic cirrhosis and the appearance of hepatocyte nodules and tumors (providing the liver has been exposed previously to initiating stimuli), diethylnitrosamine-initiated and uninitiated rats were administered thioacetamide at low dose (250 mg/l drinking water) for 6 months. Hepatocyte nodule incidence as well as changes in the drug-metabolizing system were followed at monthly intervals. In the uninitiated rats a micronodular liver cirrhosis slowly developed upon thioacetamide chronic administration; a few hepatocyte focal lesions of small size were seen from the 3rd month onward. By contrast in the diethylnitrosamine-initiated thioacetamide-treated rats the liver was macronodular because of the appearance and growth of many hepatocyte nodules; some hepatomas were also seen. During thioacetamide administration both uninitiated and diethylnitrosamine-initiated rats underwent a progressive decrease of the cytochrome P-450 liver content as well as of the activity of aminopyrine N-demethylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase. On the other hand, most components of the phase II of the drug-metabolizing system were markedly enhanced. In conclusion, chronic administration of thioacetamide at low doses provided strong promoting stimuli for previously initiated hepatocytes.
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PMID:Chronic liver injury by thioacetamide and promotion of hepatic carcinogenesis. 292 Dec 70

The effect of therapy with a microsomal enzyme-inducing drug on the cirrhotic liver in male Wistar rats was investigated by morphological and biochemical means. The cirrhotic animals were treated with medroxyprogesterone acetate (MPA) 100 mg/kg body wt, i.p. daily for a week. In the cirrhotic rats liver weight was enhanced, liver protein content was increased while total liver DNA content remained unchanged upon MPA treatment. The hepatic regenerative nodule size increased, as determined by morphological means. Hepatic microsomal metabolic activity was improved, as seen by increases in NADPH-cytochrome P-450 reductase and aminopyrine N-demethylase activities and cytochrome P-450 content. Since the increases in liver protein content and metabolic activity were relatively greater in the cirrhotic than intact animals upon MPA treatment, it was suggested that the spontaneous regeneration associated with liver cirrhosis may affect the induction phenomenon. The results demonstrate that an enzyme inducer may have beneficial effects on the cirrhotic liver by elevating metabolic activity and parenchymal mass.
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PMID:Treatment of liver cirrhosis with microsomal enzyme-inducing compound in the rat. 293 1


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