Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transglutaminase (TGase) activity in the cytosol fraction of the mouse liver increased following intraperitoneal injection of retinoic acid. Retinoic acid inhibited the carbon tetrachloride-induced increase in serum alanine transaminase activity. These findings suggest that TGase is involved in the effect of retinoic acid on carbon tetrachloride-induced liver damage.
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PMID:Effect of retinoic acid on liver transglutaminase activity and carbon tetrachloride-induced liver damage in mice. 134 64

Forty five year old male suffering from relapsed acute promyelocytic leukemia (APL) was treated with all-trans retinoic acid (ATRA) and attained second complete remission (CR) without bone marrow hypoplasia. He was diagnosed as having APL in September 1989. The DCMP-85 regimen first induced CR in October, however the disease relapsed in September 1990. The DCMP-85 and and the MEC (MIT, ETOP, Ara-C) regimens were applied for re-induction without success. Then, 45 mg/m2/day ATRA was given orally from December 28, 1990. Laboratory data before ATRA treatment were as follows; 35.4% leukemic cells in the bone marrow, Hb 11.0 g/dl, Plt 130,000/microliters, WBC 5,100/microliters without leukemic cells, and no DIC was detected. During the treatment, his bone marrow was examined frequently. The bone marrow series showed no hypoplasia at any time and gradual reduction of leukemic cells with proliferation of mature granulocytes. CR was attained on January 21, 1991. DIC did not develop. Cytogenetic anomalies including t(14;17;15) (q24;q11.2;q22) reduced from 29/30 cells at relapse to 4/30 cells at the time of CR. Dryness of mouth and lips, irritation around eyes and the elevations of GOT, GPT and triglyceride level were seen as the side effects of ATRA, however they were tolerable.
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PMID:[All-trans retinoic acid induced a complete remission in a case of refractory relapsed acute promyelocytic leukemia]. 163 77

Previously we have reported on the pigmentary lithogenic action of vitamin A in the form of retinol acetate. In the present work the possible lithogenic action of retinoic acid was tested, since this differs from retinol in several metabolic aspects, which can contribute to the understanding of the pathogenesis of the pigment cholelithiasis produced by vitamin A. Two experiments were performed in which the lithogenicity of retinol acetate added to a colony chow at the level of 25,000 IU%, was compared with that of 3 dietetic levels of all-trans retinoic acid. In the first experiment seric triglycerides were determined in order to establish whether there is a relation between the hypertriglyceridemic effect of retinoids and their lithogenicity; in the second experiment GPT and GOT were determined as indicators of hepatotoxicity. The results showed that the retinoic acid at levels of 24,000 and 35,000 IU% of diet, produced a cholelithiasis incidence similar to that of 25,000 IU% of retinol acetate, whereas the retinoic acid level of 12,000 IU% was not lithogenic. The dietetic retinoic acid produced a reduction of hepatic vitamin A, that was directly proportional to the level supplied. There was no relation between the hypertriglyceridemic effect of retinoids and its lithogenicity. The retinoids produced a light increase in GPT, which was higher with retinol acetate, whereas GOT had not significative changes. It is concluded that all-trans retinoic acid produces pigment gallstones in the hamster, with an incidence similar to that produced by retinol acetate.
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PMID:Gallstones in the golden hamster. XXXVI. Pigment cholelithiasis produced by retinoic acid. 181 96

An animal model of osteoporosis induced by retinoic acid was successfully established in 3-month-old male Wistar rats. The animals were given the drug 70 mg.kg-1.d-1 for 14 d intragastrically and sacrificed on day 29. The proximal tibia and middle tibia of the rats were processed undecalcifiedly for quantitative bone histomorphometry. Compared with the control rats, the cancellous and compact bone volume of the model rats were reduced markedly. The bone tissue microstructure showed some obvious pathological changes that the trabecular number were decreased, the separation of trabecular and medulla ossium cavity became large, the thickness of trabecular and cortex of bone were decreased. The mechanism of bone loss in the model rats was that the osteoclast was activated by retinoic acid which promoted bone resorption. Other changes in the model rats were also observed such as: the body weight, and the weights of seminal vesicle and prostate were decreased, the adrenal glands and spleen showed hyperplasia and hypertrophy. No change of the blood concentration of calcium, phosphorus, alkaline phosphatase, alanine transaminase, estradiol and testosterone in the model rats was observed.
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PMID:[A model of osteoporosis induced by retinoic acid in male Wistar rats]. 920 45

All-trans retinoic acid (ATRA) has been reported to exert major effects on the immune system, including monocytes/macrophages. The present study was designed to determine whether ATRA would modulate macrophage-associated liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS) in rats. All-trans retinoic acid administration alleviated the liver injury and reduced the incidence of death following hepatic failure. Serum alanine aminotransferase (ALT) levels 5 h after, and survival rates within 12 h after the administration of LPS were significantly lower in the ATRA-treated group (134+/-119 IU/L and 72.7%) compared with the control group (713+/-411 IU/L and 18.2%; P< 0.05). Histological findings supported these results. These effects may be due to suppression of tumour necrosis factor-alpha (TNF-alpha) and superoxide anions produced by activated macrophages. Serum levels of TNF-alpha 1 h after LPS administration were significantly lower in the ATRA-treated group (60.5+/-7.0 ng/mL) as compared with the control group (105.2+/-39.3 ng/mL; P< 0.05). Formazan deposition that was generated by the perfusion of the liver with nitroblue tetrazolium, also suggested suppression of the release of superoxide anions from hepatic macrophages. These results suggest that ATRA acts as an immunomodulator in liver injury by suppressing the activation of liver macrophages.
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PMID:All-trans retinoic acid suppresses liver injury induced by Propionibacterium acnes and lipopolysaccharide in rats. 950 2

It has been reported that there are two alternatively spliced variants of phospholipase C-delta4 (PLCdelta4), termed ALT I and II, that contain an additional 32 and 14 amino acids in their respective sequences in the linker region between the catalytic X and Y domains (Lee, S. B., and Rhee, S. G. (1996) J. Biol. Chem. 271, 25-31). We report here the isolation and characterization of a novel alternative splicing isoform of PLCdelta4, termed ALT III, as a negative regulator of PLC. In ALT III, alternative splicing occurred in the catalytic X domain, i.e. 63 amino acids (residues 424-486) containing the C-terminal of the X domain and linker region were substituted for 32 amino acids corresponding to the insert sequence of ALT I. Although the expression level of ALT III was found to be much lower in most tissues and cells compared with that of PLCdelta4, it was significantly higher in some neural cells, such as NIE-115 cells and p19 cells differentiated to neural cells by retinoic acid. Interestingly, recombinant ALT III protein did not retain enzymatic activity, and the activity of PLCdelta4 overexpressed in COS7 cells was markedly decreased by the co-expression of ALT III but not by ALT I or II. Moreover, N-terminal pleckstrin homology domain (PH domain) of ALT III alone could inhibit the increase of inositol-1,4, 5-trisphosphate levels in PLCdelta4-overexpressing NIH3T3 cells, whereas a PH domain deletion mutant could not, indicating that the PH domain is necessary and sufficient for its inhibitory effect. The ALT III PH domain specifically bound to phosphatidylinositol (PtdIns)-4,5-P2 and PtdIns-3,4,5-P3 but not PtdIns, PtdIns-4-P, or inositol phosphates, and the mutant R36G, which retained only weak affinity for PtdIns-4,5-P2, could not inhibit the activity of PLCdelta4. These results indicate that PtdIns-4,5-P2 binding to PH domain is essential for the inhibitory effect of ALT III. ALT III also inhibited PLCdelta1 activity and partially suppressed PLCgamma1 activity, but not PLCbeta1 in vitro; it did inhibit all types of isozymes tested in vivo. Taken together, our results indicate that ALT III is a negative regulator of PLC that is most effective against the PLC delta-type isozymes, and its PH domain is essential for its function.
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PMID:A novel phospholipase C delta4 (PLCdelta4) splice variant as a negative regulator of PLC. 991 23

UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosamine-1-phosphate transferase (GPT) is the first enzyme in the dolichol pathway of protein N-glycosylation, and is implicated in the developmental programmes of a variety of eukaryotes. In the present study we describe the effects of all-trans-retinoic acid (RA) on the levels of GPT protein and enzymic activity, and on the transcription rate of the GPT gene, in mouse P19 teratocarcinoma cells. RA caused a dose-dependent and protein-synthesis-dependent induction of enzyme activity. The maximum induction of GPT activity (about 3-fold) required 2 days of exposure to 1 microM RA. Induced GPT activity also resulted in an increase in the rate of incorporation of [3H]mannose into Glc3Man9GlcNAc2. Enzymic activities paralleled GPT gene expression. The GPT gene was induced (2-fold) after 7 h of RA treatment. An approx. 3-fold increase in a 48 kDa GPT protein and approx. 4-fold increases in the levels of three GPT transcripts (1.8, 2.0 and 2.2 kb) were observed after 2 days of RA treatment. The enhanced levels of GPT protein and mRNAs began to decline 3 days after the initiation of differentiation, and GPT expression was down-regulated during cellular differentiation. GPT activity decreased about 2. 8-fold to a constant level in differentiated P19 cells. The results indicate that the RA-induced enzyme activity was mainly determined by increased transcription of the GPT gene. RA-treated P19 cells were about 4-fold more resistant to tunicamycin, a fungal antibiotic which inhibits GPT, than were control cells. In addition, GPT activity in membranes from RA-treated P19 cells exhibited approx. 4-fold increased resistance to tunicamycin compared with activity in membranes from untreated control cells, demonstrating that resistance to tunicamycin is correlated with induced GPT activity. Furthermore, increased GPT activity had regulatory significance with regard to the rate of incorporation of [3H]mannose into Glc3Man9GlcNAc2-P-P-dolichol and into glycoproteins. Together, the data provide additional insights into the hormonal regulation of GPT and present evidence that the RA-mediated induction of GPT has a regulatory impact on the dolichol pathway.
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PMID:Regulation of UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosamine-1-phosphate transferase by retinoic acid in P19 cells. 1002 36

BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, and gamma. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.
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PMID:BMS-189453, a novel retinoid receptor antagonist, is a potent testicular toxin. 1115 23

We investigated the effect of transglutaminase (TGase) on in guinea pigs and rats. Serum alanine aminotransferase (ALT) level increased 1 d after CCl(4) treatment of both in guinea pigs and rats since TGaese activity was greatly higher in guinea pigs than rats. However, serum ALT level in guinea pigs was very much lower than that in rats. Liver TGase activities decreased after CCl(4) treatment in both guinea pigs and rats. However, TGase activities in the liver from guinea pigs were higher than that from rats. Decreased TGase activities by CCl(4) in the liver from guinea pigs and rats were significantly recovered by retinoic acid treatment that was reported to increase TGase. Degree of recovery of serum ALT level by retinoic acid in rats was larger than in guinea pigs. These results suggested that the distinction of the effect of retinoic acid on serum ALT level in CCl(4)-treated animals was due to the different TGase activity that increased membrane stability.
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PMID:Relationship between liver injury and transglutaminase activities in guinea pigs and rats. 1475 42

Currently used to treat severe acne, 13-cis-retinoic acid (13-cis-RA) is under investigation for its anticancer effects as is the isomer, all-trans-retinoic acid (all-trans-RA). Here, the effects of oral 13-cis-RA or all-trans-RA treatment on serum chemistry, leptin and adiponectin levels were evaluated. Adult Sprague-Dawley rats were gavaged once daily for 7 consecutive days with 13-cis-RA (7.5 or 15 mg kg(-1)), all-trans-RA (10 or 15 mg kg(-1)) (n=24/sex/dose), or soy oil (n=16/sex) and blood was sampled 30-480 min after the last gavage. The body weight was unaffected; however, the liver/body weight ratios were increased by both doses of all-trans-RA. Sex differences were noted for levels of cholesterol, creatine, triglycerides, albumin, alanine aminotransferase and total protein. Both doses of all-trans-RA reduced albumin levels to approximately 90% of the control and total protein levels to approximately 93% of the control while substantially elevating triglyceride levels to approximately 66%-99% above the control. Additionally, triglyceride levels of the 15 mg kg(-1) 13-cis RA group were approximately 62% higher than the controls and total protein levels were approximately 5% less. Glucose levels were affected by sex and RA treatment in that males treated with 15 mg kg(-1) of 13-cis-RA or 10 mg kg(-1) all-trans-RA had lower (13%-19%) levels than the same-sex controls; however, females were not similarly affected. Neither 13-cis-RA nor all-trans-RA treatment had significant effects on the levels of blood urea nitrogen, aspartate amino transferase, leptin or adiponectin. On a mg kg(-1) basis, all-trans-RA was more potent than 13-cis-RA. These results replicate previous findings of RA-induced increased triglyceride levels. Additionally, several new findings indicate there may be sex-specific effects of RA treatment. Finally, neither treatment appeared to alter the typical diurnal cycles of these endpoints.
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PMID:Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid. 1609 84


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