Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Lactic dehydrogenase (LDH), glutamic-oxalacetic transaminase (GOT), and acid and alkaline phosphatase activities in bone marrow and in cubital vein serum were compared. For patients without cancer, marrow serum LDH attained levels four times as high, and GOT and alkaline phosphatase, levels twice as high as those normal for cubital vein serum; levels of acid phosphatase were the same for both sources. For patients with cancer, significant increase of enzyme levels over reference levels depends on the tumor origin and on the presence and localization of metastases. Marrow enzyme levels may become elevated with or without concurrent elevation in cubital vein serum. Concurrent elevations were found with colonic carcinoma and lymphoid leukemia, and noncurrent elevations, with prostatic cancer, myeloid leukemia, and myeloma. A nonconcurrent elevation of marrow enzymes indicates that the origin of the enzyme is in the marrow, whereas with concurrent elevation, the source of the enzyme may be another organ.
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PMID:Enzymes in peripheral and bone marrow serum in patients with cancer. 98 36

A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.
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PMID:[Phase I study of bicalutamide (Casodex), a nonsteroidal antiandrogen in patients with prostatic cancer]. 871 91

Citrate production is a major physiological function of the prostate that is regulated by testosterone and prolactin. Mitochondrial aspartate aminotransferase (mAAT) is a key enzyme in the metabolic pathway of prostate citrate production. In addition, prolactin stimulates expression of mAAT in the rat lateral prostate. In this report we establish the role of prolactin in the regulation of mAAT in two prostate cancer cell lines, LNCaP and PC-3. LNCaP cells respond to hormonal stimulation with increased secretion of prostate specific products. PC-3 cells, on the other hand, are testosterone independent and apparently do not respond to other growth factors either. Results showed that both LNCaP and PC-3 cells responded to prolactin with increased mAAT activity and an increased steady state level of mAAT mRNA. Prolactin also increased protein kinase C (PKC) activity in both these cell lines. Treatment of LNCaP and PC-3 cells with the phorbol ester 12-O-tetradecanoylphorbol (TPA) caused the same effect on mAAT activity and mRNA level as prolactin. The results suggest that the diacylglycerol-PKC signal transduction system mediates the prolactin effect on mAAT. In addition, these results also show that the prolactin effect on mAAT is independent of androgens since PC-3 cells reportedly lack androgen receptor expression. Thus, these results provide evidence that prolactin is a physiological regulator of prostate function in human as well as rat prostate. In addition, the results also show that though prostate cancer cells are androgen independent, they remain responsive to prolactin. This could have important implications for the treatment and management of prostate cancer.
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PMID:Prolactin regulation of mitochondrial aspartate aminotransferase and protein kinase C in human prostate cancer cells. 909 97

Flutamide is a nonsteroidal antiandrogen agent. Since it was marketed in February of 1989 in the USA for treatment of prostate cancer, its potential for hepatotoxicity has been reported in Western countries. Here we report the case of a 72-year-old patient who suffered from general malaise, poor appetite, nausea and jaundice after six months of flutamide therapy for the treatment of prostate cancer. He had no past history of liver disease and was not receiving other medications. Liver biochemistries revealed elevated serum alanine aminotransferase and aspartate aminotransferase concentrations of up to 1,035 U/l and 745 U/l, respectively. Serum total bilirubin concentration was elevated to 7.0 mg/dl. Serologic markers for acute viral hepatitis were all negative. Serum antinuclear antibody, antimitochondrial antibody and antismooth-muscle antibody were also negative. Percutaneous liver biopsy revealed pericentral zonal necrosis with bridging hepatic necrosis. The patient's clinical symptoms and signs began to improve after discontinuation of flutamide, and his liver function had returned to normal three months later. Roussel Uclaf causality assessment for adverse drug reaction confirmed the diagnosis of drug-induced liver injury. This case reminds us that patients who are receiving flutamide should be regularly monitored for liver function. If drug-induced liver injury is suspected, flutamide must be discontinued promptly to avoid progression of liver injury.
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PMID:Flutamide-induced liver injury: a case report. 987 26

Severe hepatotoxicity occurred in a prostate cancer patient treated with 375 mg of flutamide per day, 125 mg three times a day, for 11 weeks. Serial measurements of serum concentrations of flutamide and its metabolites in the patient showed an unusually high serum level and delayed elimination of flutamide and suggested decreased metabolic activity of oxidation of flutamide to OH-flutamide. In 37 patients with prostate cancer we periodically monitored the serum concentrations of flutamide as well as liver function parameters. In 2 patients, glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) elevated over 100 IU/L, and treatment with flutamide was discontinued. Slight elevation of GOT and GPT over 40 to 100 IU/L was also detected in 5 patients, and flutamide was withdrawn. The elevated GOT and GPT in these 7 patients recovered to the pretreatment levels after discontinuation of the treatment. In these patients with flutamide-induced hepatic disorders, the average serum concentration of flutamide was higher (2.76 times, and that of OH-flutamide was lower (0.76 times), as compared with patients who maintained normal liver function.
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PMID:[Flutamide-induced hepatic disorder and serum concentrations of flutamide and its metabolites in patients with prostate cancer]. 1065 14

Prolactin stimulates citrate accumulation in prostate cells by increasing the expression of mitochondrial aspartate aminotransferase (mAAT). In this study, we further investigated the mechanism of prolactin regulation of mAAT expression in rat lateral prostate and LNCaP and PC-3 prostate cancer cells. Prolactin and 12-O-tetra-decanoylphorbol 13-acetate (TPA) increased the mAAT mRNA level twofold to fourfold. In addition, prolactin and TPA increased protein kinase C (PKC) activity in prostate cells 20% to 60% and 40% to 210%, respectively. The effects of both prolactin and TPA on mAAT mRNA were eliminated by downregulation of PKC. The effect of prolactin and TPA on gene transcription was determined using mAAT-chloramphenicol acetyltransferase (CAT) reporter-gene constructs, transiently transfected into PC-3 cells. The 59 untranslated region of the precursor form (pmAAT) of the mAAT gene contains five sequences that are homologous to the consensus TPA response elements (TRE). Reporter constructs with various combinations of these sequences were used to assay prolactin stimulation of CAT transcription in PC-3 cells. Prolactin increased CAT expression in PC-3 cells transfected with a reporter gene containing four of the TRE consensus sequences. Another CAT reporter gene, which contained two of the putative TREs, was also stimulated by prolactin, but a third reporter, containing the two other TRE sequences, was not induced by prolactin. These results suggest that prolactin regulates mAAT at the transcriptional level. Moreover, because both prolactin and TPA induced PKC activity, and because the effects of prolactin and TPA were eliminated when PKC was downregulated, we postulate that the prolactin effect on mAAT expression is mediated via the diacylglycerol PKC signal transduction pathway in rat lateral prostate and human prostate cancer cells.
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PMID:Protein Kinase C Mediates Prolactin Regulation of Mitochondrial Aspartate Aminotransferase Gene Expression in Prostate Cells. 1085 Dec 92

To prevent treatment withdrawal due to flutamide-induced liver dysfunction, we performed maximum androgen blockade (MAB) therapy by combining a luteinizing hormone-releasing hormone agonist or orchiectomy with low-dose flutamide (125 mg x 2/day) in patients with prostate cancer. In this study, the efficacy, adverse effects such as hepatotoxicity, and compliance were compared retrospectively between 35 patients who received low-dose flutamide therapy (1995-1999) and 27 patients who received flutamide at its ordinary dose (125 mg x 3/day). No significant difference was observed in the response rate (> or = PR) as determined from the prostate-specific antigen parameter (p = 0.6211) or the incidence of hepatotoxicity based on the aspartate aminotransferase and alanine aminotransferase levels. However, flutamide withdrawal due to liver dysfunction was less frequent in the low-dose group (2.9%) than in the ordinary dose group (18.5%) (p = 0.0386). MAB therapy using low-dose flutamide is expected to prevent the reduction in the compliance due to side effects and to improve the long-term prognosis in patients with prostate cancer, who are mostly elderly individuals.
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PMID:[Clinical efficacy of treatment with low-dose flutamide in maximum androgen blockade therapy]. 1141 Oct 99

The control and alteration of key regulatory enzymes is a determinant of the reactions and pathways of intermediary metabolism in mammalian cells. An important mechanism in the metabolic control is the hormonal regulation of the genes associated with the transcription and the biosynthesis of these key enzymes. The secretory epithelial cells of the prostate gland of humans and other animals possess a unique citrate-related metabolic pathway regulated by testosterone and prolactin. This specialized hormone-regulated metabolic activity is responsible for the major prostate function of the production and secretion of extraordinarily high levels of citrate. The key regulatory enzymes directly associated with citrate production in the prostate cells are mitochondrial aspartate aminotransferase, pyruvate dehydrogenase, and mitochondrial aconitase. Testosterone and prolactin are involved in the regulation of the corresponding genes associated with these enzymes (which we refer to as "metabolic genes"). The regulatory regions of these genes contain the necessary response elements that confer the ability of both hormones to control gene transcription. In this report, we describe the role of protein kinase c (PKC) as the signaling pathway for the prolactin regulation of the metabolic genes in prostate cells. Testosterone and prolactin regulation of these metabolic genes (which are constitutively expressed in all mammalian cells) is specific for these citrate-producing cells. We hope that this review will provide a strong basis for future studies regarding the hormonal regulation of citrate-related intermediary metabolism. Most importantly, altered citrate metabolism is a persistent distinguishing characteristic (decreased citrate production) of prostate cancer (PCa) and also (increased citrate production) of benign prostatic hyperplasia (BPH). An understanding of the role of hormonal regulation of metabolism is essential to understanding the pathogenesis of prostate disease. The relationships described for the regulation of prostate cell metabolism provides insight into the mechanisms of hormonal regulation of mammalian cells in general.
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PMID:Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. 1219 95

The caffeine test measures the activity of cytochrome p450 (CYP1A2) which is a major enzyme involved in the activation of flutamide. The usefulness of this test in predicting flutamide-induced hepatic injury in patients with prostate cancer was examined. The subjects were: (1). five patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level rose to 100 IU/l or higher following the start of flutamide (moderately injured group); (2). four patients whose AST and ALT levels were higher than normal but less than 100 IU/l (mildly injured group); and (3). two patients whose hepatic function remained normal (normal group). The subjects were each given canned coffee to drink. Urinary caffeine (137X), paraxanthine (17X) and 1, 7-dimethyluric acid (17U) levels were measured 4-5 h later. The metabolite ratio, (17U+17X)/137X, was calculated to serve as an indicator of CYP1A2 activity. The metabolite ratio for the moderately injured group (3.98+/-1.56) and the mildly injured group (5.55+/-1.42) were lower than that for the normal group (9.56). The results suggest that a decrease in CYP1A2 activity is involved in the onset of flutamide-induced hepatic injury, and that the caffeine test seems to provide a useful means of its prediction.
Prostate Cancer Prostatic Dis 2002
PMID:Caffeine test in predicting flutamide-induced hepatic injury in patients with prostate cancer. 1249 2

An examination of the change in plasma concentration of OH-flutamide in low-dose flutamide (250 mg/day) monotherapy for 5 prostate cancer patients was performed. We treated 5 patients diagnosed with prostate cancer between September and November 2002. The plasma concentrations of OH-flutamide, PSA and AST/ALT were measured before and after low-dose flutamide monotherapy was started. The plasma concentrations of OH-flutamide were stable in the third day after medication was started, and even when compared with the plasma concentrations of OH-flutamide 375 mg/day, there was no significant difference. Although at the observation period was short, PSA fell favorably in all patients. The AST/ALT were in the normal range in all patients. The low-does flutamide therapy has been one of medical treatments if its safety and effectiveness has been demonstrated.
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PMID:[Examination of the change in plasma concentration of OH-flutamide in low-dose flutamide (250 mg/day) monotherapy for prostate cancer patients]. 1504 44


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