Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The contribution of testosterone to the nephrotoxic effects of 1,2-dichloropropane (DCP) was assessed by a series of castration and sex hormone replacement experiments on Wistar rats. The nephrotoxic action of DCP was evaluated by measuring the accumulation of organic anion and release of aspartate aminotransferase into the incubation medium using a renal cortical slice model. Our data show that sex, castration, and testosterone pretreatment are factors that influence the effect of DCP on renal cortical slices of rats Males appear to be more sensitive to nephrotoxic effects of DCP than females, male castration prevents the nephrotoxic effects of DCP, and pretreatment of females and castrated males with testosterone increases the susceptibility to DCP. In this study an attempt was made to evaluate the role of sex differences in the expression of enzymes participating in Phase I and Phase II detoxication reactions in order to explain the differences in sensitivity of the two genders to the nephrotoxic action of DCP. Our results implicate gender-specific expression of cytochrome P-450 in the kidneys as a predominant factor that determines the different susceptibilities of male and female rats to the nephrotoxic effect of DCP. We propose that the oxidation of DCP by CYP IIE1 is the first saturable and limiting step in the metabolic activation of DCP to nephrotoxic metabolites. It appears that, despite the fact that the nephrotoxic effect of DCP is determined mainly by its cysteine-conjugated metabolites, gluthathione (GSH) content and glutathione S-transferase (GST) activity in kidney are not directly related to increased androgen-related susceptibility to DCP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of sex-related differences in nephrotoxicity of 1.2-dichloropropane in rats. 857 Aug 64

Enflurane is a fluorinated volatile anesthetic, mostly eliminated unchanged in exhaled air. About 10% of inhaled enflurane undergoes oxidative metabolism in liver via mixed function oxidase. We examined the influence of ethanol and subchronical exposition (6 hours a day, during five consecutive days) to subanesthetic and anesthetic concentrations of enflurane on liver function in BALB/c mice. Specially designed chamber for inhalatory application of anesthetics was constructed for this study. Animals were divided in six groups of twenty. The ethanol treated group was injected with ethanol intraperitoneally (1 g/kg). Two enflurane treated groups were intraperitoneally injected with 0.9% solution of sodium chloride (10 ml/kg) and one of them exposed to subanesthetic (0.5 Vol%) and the other one to anesthetic (2.75 Vol%) concentrations of enflurane. Following two groups received ethanol (1 g/kg) and each of them inhaled enflurane at previously mentioned doses. The control group was intraperitoneally injected with 0.9 % solution of sodium chloride (10 ml/kg) and did not receive any anesthetic. On the day following the last day of exposure half of the animals from each group were sacrificed for determination of glucose levels, erythrocyte glutathion levels, haematocrit, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), liver protein and glutathion levels, and total cytochrome P-450 (CYP P-450). The other half of animals from each group were injected intraperitoneally with caffeine (20 mg/kg). Caffeine and its metabolites in 8 hour urine were analyzed by high performance liquid chromatography (HPLC) method. Excretion of caffeine and its metabolites was different among the groups. We followed two caffeine metabolic ratios - 1,3-dimethyl uric acid and 3,7-xanthine (1,3-U/3,7-X) and 3,7-dimethyl xanthine + 7-xanthine and 1-xanthine + 1,7-dimethyl uric acid (3,7-X + 7-X/1-X + 1,7-U). The difference in caffeine metabolites ratios suggests that enflurane changes oxidative metabolism in liver via certain subtypes of mixed function oxidase, probably via CYP-4502E1. This effect is more expressed when ethanol and enflurane are applied together. Ethanol is well known inductor of CYP-4502E1 and the registrated enzyme induction could be explained by both influences - of ethanol and enflurane.
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PMID:The influence of anesthetic concentrations of enflurane and ethanol on caffeine metabolism in mice. 1044 95

The aim of this study was to investigate the effects of trauma on alterations in cytochrome P450 (CYP 450)-dependent drug metabolizing function and to determine the role of Kupffer cells in hepatocellular dysfunction. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia, while control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl3) was injected intravenously via the tail vein at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h after FFx, serum alanine aminotransferase (ALT) activity was increased, and this increase was attenuated by GdCl3 pretreatment. Serum aspartate aminotransferase (AST) and lipid peroxidation levels were not changed by FFx. Hepatic microsomal CYP 450 content and aniline p-hydroxylase (CYP 2E1) activity were significantly decreased; decreases that were not prevented by GdCl3. The level of CYP 2B1 activity was decreased by Kupffer cell inactivation, but not by FFx. There were no significant differences in the activities of CYP 1A1, CYP 1A2 and NADPH-CYP 450 reductase among any of the experimental groups. Our findings suggest that FFx trauma causes mild alterations of hepatic CYP 450-dependent drug metabolism, and that Kupffer cells are not essential for the initiation of such injury.
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PMID:The roles of Kupffer cells in hepatocellular dysfunction after femur fracture trauma in rats. 1256 58

Primary rat hepatocytes were cultured using different in vitro models and the enzyme leakage, albumin secretion, and cytochrome P450 1A (CYP 1A) activity were observed. The results showed that the level of LDH was decreased over time in culture. However, on day 5, LDH showed a significant increase in monolayer culture (MC) while after day 8 no LDH was detectable in sandwich culture (SC). The levels of AST and ALT did not change significantly over the investigated time. The CYP 1A activity was gradually decreased in a time-dependent manner in MC and SC. The decline of CYP 1A was faster in MC than in SC. This effect was partially reversed by using cytochrome P450 (CYP450) inducer such as Omeprazol and 3-methylcholanthrene (3-MC) and the CYP 1A induction was always higher in MC than in SC. In bioreactor basic CYP 1A activity was preserved over 2 weeks and the highest albumin production was observed in bioreactor followed by SC and MC. Taken together, it was indicated each investigated model had its advantages and disadvantages. It was also underlined that various in vitro models may address different questions.
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PMID:Qualitative study of three cell culture methods. 1267 60

Primary rat hepatocytes were cultured using three kinds of models in vitro and the enzyme leakage, albumin secretion, and cytochrome P450 1A (CYP 1A) activity were observed. The results showed that the level of LDH in the medium decreased over time in the period of culture. However, on 5 days, LDH showed a significant increase in monolayer culture (MC) while after 8 days LDH was not detected in sandwich culture (SC). The levels of AST and ALT in the medium did not change significantly over the investigated time. The basic CYP 1A activity gradually decreased with time in MC and SC. The decline of CYP 1A in rat hepatocytes was faster in MC than that in SC. This effect was partially reversed by using cytochrome P450 (CYP450) inducers such as omeprazol and 3-methylcholanthrene (3-MC) and the CYP 1A induction was always higher in MC than that in SC. Basic CYP 1A activity in bioreactor was keeped over 2 weeks and the highest albumin production was observed in bioreactor, and next were SC and MC. In conclusion, our results clearly indicated that there have some advantages and disadvantages in each of models in which can address different questions in metabolism of toxicants and drugs.
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PMID:[Effect evaluation of three cell culture models]. 1496 96

Hepatotoxic effect of (+)usnic acid, the active constituent of Usnea siamensis Wainio was studied in rats, isolated rat hepatocytes and isolated rat liver mitochondria. In rats, after treatment with high dose of (+)usnic acid (200 mg/kg per day, i.p.) for 5 days, there was no significant change in serum transaminase activity (serum AST, ALT) while the electron micrographs showed apparent morphological damage of mitochondria and endoplasmic reticulum. (+)Usnic acid at high dose (1 mM) as well as carbon tetrachloride (CCl4, the reference hepatotoxin) induced loss of cell membrane integrity in isolated rat hepatocytes by increasing the release of cellular transaminases (AST, ALT). Increase in lipid peroxidation, decrease in glutathione (GSH) content and increase in aniline hydroxylase activity (CYP 2E1) were also found. Combination of (+)usnic acid and CCl4 showed the additive results. (+)Usnic acid (0.15-6 microM) possessed uncoupling activity in isolated rat liver mitochondria. It stimulated respiration by mitochondria respiring with glutamate plus malate or succinate as substrates and activated ATPase activity. Increasing concentration of (+)usnic acid (>6 microM) exhibited loss of respiratory control and ATP synthesis. In conclusion, hepatotoxic effect of high dose (+)usnic acid may involve its reactive metabolite(s), causing loss of integrity of membrane like structures, resulting in destruction of mitochondrial respiration and oxidative phosphorylation.
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PMID:Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. 1501 5

The xylenes are commonly used industrial solvents that have been shown to inhibit cytochrome P-450 (CYP450) activities in an organ- and isozyme-specific pattern. This study examined the dose-response and durational effects of m-xylene inhalation on cytochrome P-450 activities in the respiratory tract and liver as well as the effects of these CYP450 alterations on 1-nitronaphthalene (1-NN)-induced respiratory or hepatic toxicity. After m-xylene inhalation exposure there was a dose-related inhibition of all nasal mucosa CYPs examined. At 300 ppm, inhibition was sustained up to 2 days after exposure, but on day 5 all CYP activities were increased. There was also dose-related inhibition of lung CYPs 2B1, 2E1, and 4B1. The activities of these CYPs returned to those of control by day 2 but lung CYP 2B1 was increased 5 days following m-xylene exposure. Hepatic CYP 2E1 activity was increased immediately following m-xylene exposure (300 ppm). CYP 2B1 and CYP 1A2 activities were increased through day 2, all activities returning to control values 5 days postexposure. 1-NN treatment caused severe respiratory toxicity that was prevented by prior m-xylene exposure. Lactate dehydrogenase (LDH) and protein were increased in nasal lavage fluid (NLF) but gamma-glutamyl transferase (GGT) was unchanged. m-Xylene coexposure prevented or ameliorated the increases in LDH and protein but increased GGT. 1-NN-induced increases in bronchoalveolar lavage fluid (BALF) LDH and GGT were attenuated by m-xylene. 1-NN caused pronounced histopathological changes in both respiratory and olfactory regions of the nasal mucosa. Lesions in both regions were characterized by acute epithelial necrosis and exfoliation and suppurative exudate in the airways. These changes were prevented by m-xylene coexposure. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were not changed in animals exposed to 1-NN but were increased by m-xylene coexposure. Low-level m-xylene exposure organ-selectively altered CYP450 isozyme activities and subsequent 1-NN toxicity.
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PMID:Inhibition of rat respiratory-tract cytochrome P-450 activity after acute low-level m-xylene inhalation: role in 1-nitronaphthalene toxicity. 1520 73

We carried out this experiment to evaluate the relationship between isoforms of cytochrome P450 (P450) and liver injury in lipopolysaccharide (LPS)-induced endotoxemic rats. Male rats were intraperitoneally administered phenobarbital (PB), a P450 inducer, for 3 days, and 1 day later, they were intravenously given LPS. PB significantly increased P450 levels (200% of control levels) and the activities (300-400% of control) of the specific isoforms (CYP), CYP3A2 and CYP2B1, in male rats. Plasma AST and ALT increased slightly more in PB-treated rats than in PB-nontreated (control) rats with LPS treatment. Furthermore, either troleandomycin or ketoconazole, specific CYP3A inhibitors, significantly inhibited LPS-induced liver injury in control and PB-treated male rats. To evaluate the oxidative stress in LPS-treated rats, in situ superoxide radical detection using dihydroethidium (DHE), hydroxy-2-nonenal (HNE)-modified proteins in liver microsomes and 8-hydroxydeoxyguanosine (8-OHdG) in liver nuclei were measured in control and PB-treated rats. DHE signal intensity, levels of HNE-modified proteins, and 8-OHdG increased significantly in PB-treated rats. LPS further increased DHE intensity, HNE-modified proteins, and 8-OHdG levels in normal and PB-treated groups. CYP3A inhibitors also inhibited the increases in these items. Our results indicate that the induction or preservation of CYP isoforms further promotes LPS-induced liver injury through mechanisms related to oxidative stress. In particular, CYP3A2 of P450 isoforms made an important contribution to this LPS-induced liver injury.
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PMID:CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats. 1528 27

Our goal was to elucidate roles of Nrf2 in in vivo defense against pentachlorophenol (PCP), an environmental pollutant and hepatocarcinogen in mice. We examined oxidative stress and cell proliferation, along with other hepatotoxicological parameters, in the livers of nrf2-deficient (wild:+/+, heterozygous:+/-, homozygous:-/-) animals fed PCP in their diet at doses of 0, 150, 300, 600, or 1200 ppm for 4 weeks. For measurement of methoxyresorufin-O-demethylase (CYP 1A2), NAD(P):quinone oxidoreductase 1 (NQO1), and UDP-glucuronosyltransferase (UDP-GT), an additional study was performed with all but the 150-ppm dose. Significant elevation of 8-hydroxydeoxyguanosine (8-OH-dG) levels in the liver DNA was observed only in -/- mice treated with PCP at 1200 ppm. Levels of thiobarbituric-acid-reactive substances (TBARS) were also raised significantly compared to those of the relevant +/+ mice. Bromodeoxyuridine labeling indices (BrdU-LIs) of hepatocytes in -/- mice were significantly higher at all doses than those in the relevant +/+ mice. Relative liver weights were unchanged in mice lacking Nrf2, whereas liver weight in +/+ and +/- mice was increased. Significant elevations of serum ALP activity, but not ALT and AST activity, occurred at 600 ppm and above in -/- mice compared to the relevant +/+ mice. Histopathologically, centrilobular hepatocyte necrosis was severe in the -/- mice that received 600 ppm. Although CYP 1A2 activity was elevated in all treated mice, increases in NQO1 levels and UDP-GT activities did not occur only in -/- mice. These data suggest that Nrf2 plays a key role in prevention of PCP-induced oxidative stress and cell proliferation.
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PMID:A crucial role of Nrf2 in in vivo defense against oxidative damage by an environmental pollutant, pentachlorophenol. 1635 18

It has been reported that malaria infection impairs hepatic drug clearance and causes a down-regulation of CYP-mediated monooxygenase activities in rodents and humans. In the present study, we investigated the effects of Plasmodium berghei infection on the activity of liver monooxygenases in female DBA/2 and C57BL/6 mice. In both mouse strains, P. berghei infection decreased activities mediated by CYP1A (EROD: DBA/2 65.3%, C57BL/6 44.7%) and 2B (BROD: DBA/2 64.3%, C57BL/6 49.8%) subfamily isoforms and increased activities mediated by 2A5 (COH: DBA/2 182.4%, C57BL/6 148.5%) and 2E1 (PNPH: DBA/2 177.8%, C57BL/6 128.5%) isoforms as compared to non-infected controls. Since malaria infection also produced an increase in ALT (273.1%) and AST (354.1%) activities in the blood serum, our findings are consistent with the view that CYP2A5 activity is induced by liver injury. An almost generalized depression of CYP-mediated activities has been found with numerous infections and inflammatory stimuli but an induction of CYP2A5 had been previously noted only in some viral hepatitis and trematode (liver fluke) infections.
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PMID:Plasmodium berghei (ANKA): infection induces CYP2A5 and 2E1 while depressing other CYP isoforms in the mouse liver. 1654 Jan 9


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