Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic failure is frequently seen following severe hemorrhagic shock, sepsis, and trauma. Clearance of various drugs has been used to evaluate hepatocellular dysfunction, including indocyanine green (ICG), an organic anionic dye that is transported similarly to bilirubin, and antipyrine (AP), a marker of oxidative phosphorylation. Previous investigators have noted a decrease in ICG excretion following systemic hemorrhage. The effect of isolated hepatic ischemia on the clearances of ICG and AP was studied in 16 pigs after 90 minutes of vascular occlusion to the liver. Antipyrine clearance decreased almost 50% from baseline values at 24 and 72 hours after the ischemia procedure, indicating a significant depression in the cytochrome P-450 system. On the other hand, ICG clearance did not change significantly. In conclusion, ICG clearance is not depressed after isolated hepatic ischemia in pigs. Changes in organic anion clearance after systemic hemorrhage may be because of release of toxic products from ischemic peripheral tissue.
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PMID:Effect of isolated hepatic ischemia on organic anion clearance and oxidative metabolism. 156 25

This study was done to determine the relationship between microsomal lipid peroxidation during hepatic ischemia/reperfusion and alteration in cytochrome P-450-dependent drug metabolism. Rats were pretreated with alpha-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham-ischemic animals. After 1, 5 or 24 hr of reperfusion, liver microsomes were isolated and cytochrome P-450 and mixed function oxidases were studied. In vehicle-treated ischemic rats, serum ALT levels peaked at 5 hr (5,242 +/- 682 U/L) and were significantly reduced by alpha-tocopherol pretreatment (1,854 +/- 229 U/L, p less than 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle-treated ischemic group, but this elevation was prevented by alpha-tocopherol pretreatment. Microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity were both decreased in vehicle-treated ischemic rats to 60% and 70% of sham-ischemic control levels, respectively. Although alpha-tocopherol restored cytochrome P-450 content to the level of sham-ischemic control rats, aminopyrine-N-demethylase activity remained at 76% of control with alpha-tocopherol treatment (p less than 0.01 compared with sham-ischemic control). In contrast to what was seen with cytochrome P-450 and aminopyrine-N-demethylase, aniline p-hydroxylase activity was elevated in the vehicle-treated ischemic rats compared with sham-ischemic control rats. These increases were prevented by alpha-tocopherol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of alpha-tocopherol on hepatic mixed function oxidases in hepatic ischemia/reperfusion. 173 30

The effects of Bifemelane (BF) on lipid peroxidation, the activities of hepatic drug metabolizing enzymes, and the function of cell membranes were examined in rats. In the liver ischemia-reperfusion model, BF suppressed the elevation of the lipid peroxidation level during the period of reperfusion. BF did not exhibit a radical-trapping action using a stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH), which was estimated by electron spin resonance (ESR). BF remarkably inhibited NADPH-dependent lipid peroxidation in vitro. BF had no effect on the contents of cytochrome P-450 and b5 and the activities of NADPH cytochrome P-450 reductase and Cu,Zn-superoxide dismutase (SOD). BF suppressed phorbol myristate acetate (PMA)-induced superoxide formation of polymorphonuclear leukocytes (PMNs), protected hypotonic hemolysis of erythrocyte and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and serum phospholipase A activity. These results suggest that BF has neither radical-trapping activity nor any influence on the drug metabolizing enzymes, but BF has a membrane-stabilizing action and it attributes to the suppressive effect of lipid peroxidation.
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PMID:Suppressive effect of bifemelane on lipid peroxidation in rat liver. 215 22

Reactive oxygen species are a major cause of damage occurring in ischemic tissue after reperfusion. During reperfusion transitional metals such as iron are required for reactive oxygen species to mediate their major toxic effects. Xanthine oxidase is an important source of reactive oxygen species during ischemia-reperfusion injury, but not in all organs or species. Because cytochrome P-450 enzymes are an important pulmonary source of superoxide anion (O2-.) generation under basal conditions and during hyperoxia, and provide iron catalysts necessary for hydroxyl radical (.OH) formation and propagation of lipid peroxidation, we postulated that cytochrome P-450 might have a potential role in mediating ischemia-reperfusion injury. In this report, we explored the role of cytochrome P-450 enzymes in a rabbit model of reperfusion lung injury. The P-450 inhibitors 8-methoxypsoralen, piperonyl butoxide, and cimetidine markedly decreased lung edema from transvascular fluid flux. Cimetidine prevented the reperfusion-related increase in lung microvascular permeability, as measured by movement of 125I-albumin from the vascular space into lung water and alveolar fluid. P-450 inhibitors also prevented the increase in lung tissue levels of thiobarbituric acid reactive products in the model. P-450 inhibitors did not block enhanced O2-. generation by ischemic reperfused lungs, measured by in vivo reduction of succinylated ferricytochrome c in lung perfusate, but did prevent the increase in non-protein-bound low molecular weight chelates of iron after reperfusion. Thus, cytochrome P-450 enzymes are not likely a major source of enhanced O2-. generation, but serve as an important source of iron in mediating oxidant injury to the rabbit lung during reperfusion. These results suggest an important role of cytochrome P-450 in reperfusion injury to the lung and suggest potential new therapies for the disorder.
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PMID:Role of cytochrome P-450 in reperfusion injury of the rabbit lung. 217 18

Hepatic ischemia induced in vivo by ligation of the left hepatic lobe of rats for up to 2 hr had no effect on cytochrome P-450, cytochrome c reductase, or lobe histology; however, cytochrome b5 increased with ischemia duration. Ethylmorphine demethylation decreased 35% after 2 hr of ischemia. Reperfusion of tissue previously made ischemic for up to 2 hr was associated with appreciable necrosis as well as decreases in cytochrome P-450, cytochrome b5, cytochrome c reductase, and ethylmorphine demethylation. Serum alanine transaminase and aspartate transaminase concentrations were increased by reperfusion of previously ischemic tissue. Reperfusion of the previously ischemic lobe for 18 hr was associated with a greater loss of cytochromes P-450 and b5, cytochrome c reductase, and ethylmorphine demethylation than reperfusion for 1 hr. The total decrease in cytochrome P-450 and b5 content was equal to the decrease in total microsomal heme content, although cytochrome P-450 decreased more than cytochrome b5. Ethoxyresorufin deethylation by hepatic microsomes from 3-methylcholanthrene-treated rats was decreased by ischemia-reperfusion; however, pentoxyresorufin dealkylation by hepatic microsomes from phenobarbital-treated rats was not, suggesting specific cytochrome P-450 isozyme loss. In vitro NADPH-dependent lipid peroxidation in hepatic microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats resulted in a selective decrease of ethoxyresorufin but not pentoxyresorufin dealkylation, similar to that observed in livers subjected to ischemia-reperfusion in vivo. These data suggest that cytochrome P-450, ethylmorphine demethylation, and ethoxyresorufin deethylation are more susceptible to ischemia-reperfusion injury than cytochrome b5 or pentoxyresorufin dealkylation.
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PMID:Effects of hepatic ischemia-reperfusion injury on the hepatic mixed function oxidase system in rats. 225 Jun 63

In the liver ischemia-reperfusion model, the lipid peroxide level increased during ischemic periods, while a greater increase was observed during reflow periods. The increase in the cytochrome b5 content was observed during ischemia and reflow periods. On the contrary, the cytochrome P-450 content remained unchanged during ischemic periods, but decreased during reflow periods. Bifemelane suppressed the elevation of the lipid peroxide level, the cytochrome b5 content and the decrease in cytochrome P-450 content during the period of reperfusion.
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PMID:Effect of bifemelane hydrochloride on an injury of the liver caused by ischemia-reperfusion in rats. 231 43

DNA synthesis was studied in liver nuclei of Wistar rats after 30% liver tissue resection, 2 hr ischemia of 70% liver tissue or 2 hr ischemia of 70% liver tissue with resection of intact lobes. DNA synthesis was markedly increased in ischemic lobes and was especially high in ischemic lobes if simultaneous resection of intact lobes occurred; maximum of the synthesis was observed within 32 hrs after the operation. Proliferation stimulating extracts, isolated from liver tissue within 48 hrs after the resection or after ischemia, intensified the regenerating processes in the resected liver tissue; the first preparation (from resected liver tissue) exhibited the most distinct effect as compared with the second extract (from ischemic liver tissue). Proliferation stimulating extracts did not affect the cytochrome P-450, content of which was decreased after resection and ischemia. The data obtained suggest the important role of proliferation stimulating factors in regeneration of liver tissue after ischemia or resection; these factors proved to be possible to isolate from ischemized and reperfused liver tissue; the medicinal effect of resection was shown.
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PMID:[Regeneration ability of ischemic liver and the effect of liver resection and extracts stimulating proliferation]. 274 22

A previously validated small mammal trauma model, hindlimb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on two of the major hepatic enzymes of detoxification, glutathione S-transferase and epoxide hydrolase. Hepatic cytosolic glutathione S-transferase activity toward a variety of substrates showed a 26-34% decrease at 24 hr after model injury. Hepatic microsomal epoxide hydrolase activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was diminished by 53% after model trauma. Both enzymatic activities toward styrene oxide were similarly depressed. The toxicological sequelae of these derangements were illustrated by administering a dose of styrene oxide (300 mg/kg, ip) which was below the threshold dose (350 mg/kg, ip) necessary to produce hepatotoxicity in control animals. Model trauma dramatically enhanced the hepatotoxic effects of the subthreshold dose, as well as the covalent binding of labeled styrene oxide to liver proteins. These findings indicate that traumatic injury renders the animal more susceptible to agents which are detoxified by glutathione S-transferase and epoxide hydrolase. Conversely, model trauma provided almost complete protection from the hepatotoxic effects of a standard dose (200 mg/kg, ip) of bromobenzene. This protection appeared to derive from a post-traumatic alteration of cytochrome P-450 subpopulations that decreased the formation of the potentially toxic 3,4-epoxide metabolite, despite an increase in the cytochrome P-448-mediated generation of the nontoxic 2,3-epoxide. For bromobenzene, the change in cytochrome P-450-mediated activation appeared quantitatively more significant in overall toxicity than the post-traumatic depression of detoxification pathways described above, leading to decreased toxicity in vivo. For other compounds, the combination of post-traumatic influences on cytochrome P-450/P-448 activity and epoxide hydrolase/glutathione S-transferase activities could lead to markedly enhanced toxicity.
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PMID:Effects of model traumatic injury on hepatic drug metabolism in the rat. VI. Major detoxification/toxification pathways. 289 98

Leukotriene B4 was found to be metabolized by rat hepatocyte monolayers at a rate that was linear with increasing substrate concentration from 74 to 740 nM leukotriene B4. The rates of metabolism were dependent on the O2 concentration and were 315, 213, 80, and 36 pmol leukotriene B4 per min per nmol cytochrome P-450 at 20% (212 microM), 4% (42.5 microM), 2% (21.2 microM), and 1% (10.6 microM) O2, respectively. The metabolic rate was not linear with respect to O2 concentration; however, half maximal rate occurred at 4% O2, and O2 concentration found in the pericentral region of normally oxygenated liver. These results suggest that in vivo conditions of hypoxia or ischemia that lead to blood O2 concentrations less than 4% may drastically decrease hepatic clearance of leukotriene B4.
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PMID:Oxygen concentration-dependent metabolism of leukotriene B4 by hepatocyte monolayers. 301 10

Total ischemia of rat liver tissue within 30 min caused distinct alterations in lipid component of endoplasmic reticulum membranes, which occurred within three weeks of the postischemic period. During this period the rate of microsomal lipids saturation was elevated due to an increase in the relative content of saturated fatty acids. Two-step alterations were observed in the patterns of fluorescent probe binding (I-amino naphthalene-8-sulfonate) as well as in sensitivity of cytochrome P-450 to the impairment in vitro after induction of lipid peroxidation in microsomal membranes. Within 1-3 days after the ischemia affinity of the fluorescent probe to microsomes was decreased, while stability of cytochrome P-450 to impairment during lipid peroxidation induction was increased. Within 7-14 days affinity of the fluorescent probe to membranes was markedly elevated and stability of cytochrome P-450 to the impairment in vitro was lowered in the reactions of lipid peroxidation.
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PMID:[Structural changes in the lipid component of membranes of endoplasmatic reticulum in early and late periods after liver ischemia]. 336 23


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