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

Cytotoxicity and apoptosis are common problems in the isolation and storage of human hepatocytes. In vitro environments of hepatocytes during cell infusion may be critical to reducing cellular damage and enhancing cell viability. We examined the effects of donor liver histology (40-50% steatosis vs. normal), incubation time, temperature, and three solutions for infusion on banked primary human hepatocytes, by studying: trypan blue exclusion, AST release, LDH release, MTT assay, detection of DNA ladder, and a hepatocyte proliferation assay. In addition, the microstructure functions of the endoplasmic reticulum and mitochondria of the intact hepatocytes were determined by measuring correlates of UGT 1A1 and cytochrome P-450 3A (CYP3A4) activity. In general, hepatocyte viability decreased significantly within 60 min after thawing. Cells suspended in 5% dextrose lactated Ringers solution (D5LR) maintained greater cell viability. Hepatocytes from normal liver donors showed less AST and LDH enzyme leak in comparison with cells from fatty liver donors. Mild hypothermic temperature (32 degrees C) inhibited cellular damage that otherwise significantly increased at 60 min. Hepatocytes did not proliferate until 12 h from thaw, regardless of supernatant or conditions of suspension. CYP3A4 activity and a marker for UGT 1A1 activity in hepatocytes from normal donor livers were higher than those from steatotic donor livers. These findings suggest that hepatocytes suspended for infusion after isolation from normal liver donors have normal biological functions and less cellular damage/necrosis in contrast with those isolated from fatty liver donors. These damages are inhibited significantly by maintaining hepatocytes at a mild hypothermic temperature (32 degrees C). D5LR alone maintained the best cell viability for up to 60 min. Media of D5LR + adenosine and HMM were able to partially inhibit hepatocyte apoptosis in hepatocytes from steatotic livers.
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PMID:Optimization of conditions for clinical human hepatocyte infusion. 1564 38

Standard toxicologic endpoints, supplemented by additional examinations, were studied for groups of 10 Fischer 344 rats/sex given drinking water formulated to supply 0, 50, 250, or 1000 mg diethylene glycol monobutyl ether (DGBE)/kg/day for 13 weeks. These dose levels were based upon initial investigations using drinking water formulated to supply 0, 1000, 1500 or 2000 mg DGBE/kg/day for two weeks. All rats survived the respective treatment intervals with no adverse treatment-related in-life effects, including no alterations in a functional observational battery. In both studies, rats given > or = 1000 mg/kg/day consumed less water and feed and weighed slightly less than controls. For rats given > or = 1000 mg DGBE/kg/day, the liver and red blood cells (RBC) were the primary target organs although the effects were slight. In the 13-week study, rats given 1000 mg/kg/day had statistically significant increased relative liver weight (7-10%) and hepatic cytochrome P450s (24-39%) and UGT (approximately 16%) levels along with slight, statistically significant, decreases in serum total protein, cholesterol and aspartate aminotransferase. Histopathologically, very slight hepatocyte hypertrophy and increased individual hepatocyte degeneration were found in females only. At 1000 mg/kg/day, the RBC count, hemoglobin (Hgb) and hematocrit (Hct) were minimally, but statistically significantly, decreased (5.1-8.7%) but RBC morphology, RBC indices, reticuloctye count and bone marrow and spleen histopathology were unaffected. Absolute and relative kidney weights statistically significantly increased (6-13%) with an equivocal increase in minor histopathologic changes typical of early spontaneous nephropathy. There were no adverse effects on urinalysis, clinical chemistry, sperm parameters or testis histopathology. At 250 mg/kg/day, there were equivocal decreases (approximately 2-3%) in RBC count, Hgb and Hct that were statistically significant for the RBC count and Hgb, but these changes were within the historical control range. This dose level was considered the no adverse effect level (NOAEL).
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PMID:Diethylene glycol monobutyl ether (DGBE): two- and thirteen-week oral toxicity studies in Fischer 344 rats. 1568 Jun 84

Xuefu Zhuyu decoction (XFZYD) is a famous traditional Chinese medicine (TCM) formula, is widely used in the treatment of cardiovascular and cerebrovascular diseases in China over one hundred years. But its effect on antioxidant and drug-metabolizing enzymes are unknown. This study was to observe the effects of Xuefu Zhuyu decoction (XFZYD) on the activities of antioxidant and drug metabolism enzymes (DMEs) in liver of rats. Male SD rats, treated with XFZYD at the dosage of 3.51, 7.02 and 14.04 g x kg(-1) per day for 15 days, serum were collected, tissue fluid, cytosols and microsomes isolated from liver tissues were prepared by centrifugation according to the standard procedure, the activities of antioxidant enzymes and drug-Metabolizing Enzymes were determined by UV-V is spectrophotometer. In serum, the activities of AST was not significantly affected by the treatment with XFZYD, at the high- est dose, the levels of ALT, Cr and BUN were significantly decreased (P < 0.05). GPX were significantly increased at the dose of 7.02, 14.04 g x kg(-1) (P < 0.05), CAT were significantly increased at the highest dose (P < 0.05). T-SOD was not significantly af- fected by this treatment. In the liver tissue, GPX was significantly increased at the dose of 3.51, 7.02 g x kg(-1) (P < 0.05), GST, CAT and T-SOD were not significantly affected following this treatment. In cytosols, GST was significantly increased at the dose of 3.51 g x kg(-1) (P < 0.05), T-SOD was remarkable induced at the dose of 3.51 and 7.02 g x kg(-1) (P < 0.05). In microsomes, XFZYD had no significant effect on Cytochromeb5, NADPH-Cytochrome P450 reductase, CYP3A, CYP2E1 and UGT, XFZYD significantly in- duced GST at the dose of 3.51 and 7.02 g x kg(-1) (P < 0.05), and the level of GSH were significantly increased by XFZYD at the dose of 3.51, 7.02 and 14.04 g kg(-1) (P < 0.05). These findings suggest XFZYD can induce the activities of GPX, CAT, SOD, GST and increase GSH level in liver of rats, which indicate XFZYD may have detoxification and antioxidant functions.
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PMID:[Effects of xuefu zhuyu decoction on antioxidant and drug-metabolizing enzymes in liver of rats]. 2585 Feb 84

This study aimed to explore the effects of genistein on regulating the activation of UGTs via the Nrf2/Keap1 pathway and to elucidate the underlying mechanisms of detoxification and hepatic protection. Experiments monitoring genistein-induced protection against acetaminophen-induced cell damage were performed in L-02, HepG2 and Hep3b cells. The results of the MTT, AST, ALT, LDH, GSH and GSSG assays showed that genistein evidently protected the cells from acetaminophen-induced injury in a dose-dependent manner. The control cells were treated with 10 mM acetaminophen without genistein to compare with the effects of the combination of acetaminophen and genistein on the expression of UGT1A1, 1A6 and 1A9, Nrf2 and Keap1 mRNAs, as well as the expression of Nrf2 and Keap1 proteins, which were tested by western blotting. The results showed that the expression of the Nrf2 mRNA and protein increased; in contrast, the expression levels of the Keap1 mRNA and protein were obviously reduced by genistein in a dose-dependent manner. Meanwhile, the expression of the UGT mRNA was increased, and UGT1A9 exhibited the highest expression among the three UGTs. Accordingly, the residual acetaminophen content was obviously reduced and acetaminophen glucuronidation increased after 24 hours of treatment with genistein in a dose-dependent manner.
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PMID:Genistein promotes the metabolic transformation of acetaminophen to glucuronic acid in human L-O2, HepG2 and Hep3b cells via the Nrf2/Keap1 pathway. 2778 Dec 31