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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The early effects of 4'-epidoxorubicin (Epi-Adriamycin) on liver regeneration and late effects on liver function were studied after a standard partial hepatectomy in rats. 4'-epidoxorubicin was given intravenously immediately preoperatively. Neither suppression nor delay in DNA synthesis (analyzed by incorporation of 3H-thymidine) during the first 72 h postoperatively was registered after a dose of 5 mg/kg body weight. Four weeks following the dose of 5 mg/kg a slight decrease was found in liver weight (8%), body weight (8%) and plasma albumin values (9%) compared with the partial hepatectomized controls. Total protein, alkaline phosphatase, total bilirubin and alanine aminotransferase were not changed. A dose of 2 mg/kg did not alter any of the parameters. No histological signs of liver and kidney damage were seen. The results indicate that preoperative treatment with 4'-epidoxorubicin combined with partial hepatectomy may possibly be used in humans without clinically significant impairment of liver regeneration and function of the remaining liver and without histological detectable nephrotoxicity. The dosage of 4'-epidoxorubicin must, however, be adjusted according to species differences in pharmacokinetics.
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PMID:Effect of preoperative 4'-epidoxorubicin (epi-adriamycin) treatment on the regeneration and function of the liver in partially hepatectomized rats. 280 48

Adriamycin, an anticancer drug, caused dramatic increases in the serum lipid levels of rats fed a high-cholesterol diet. Male Lewis inbred rats were fed a basal or 1.5% cholesterol diet containing 0.5% cholic acid for 8 weeks. The rats were injected with adriamycin in doses of 1.5 mg/kg body weight, twice a week, and 6.0 mg/kg body weight, every other week. The serum lipid peroxide level gradually rose in adriamycin-treated rats, reaching a four-fold level at the end of the experiment. Cholesterol feeding, however, had a lowering effect on the lipid peroxide level. Adriamycin treatment or cholesterol feeding moderately elevated serum lipid levels, but their combination exerted a synergistic effect. In rats injected with a large dose of adriamycin and fed a high-cholesterol diet, the serum cholesterol, triglyceride and phospholipid levels strikingly increased by approx. 2000, 1500 and 1300 mg/100 ml, respectively. However, the ester ratio of cholesterol remained almost constant. Furthermore, serum GOT, GPT and ALP activities were only slightly different from the control values. Adriamycin treatment produced severe hypoalbuminemia. Ascites was also observed in rats given a large dose of adriamycin. The present findings indicate that the hyperlipidemia we observed may basically result from adriamycin-induced nephrosis and can be markedly enhanced when rats are fed a high-cholesterol diet. In spite of remarkably high levels of serum lipids and lipid peroxides, the aortic cholesterol level increased only slightly.
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PMID:Hyperlipidemic effects of adriamycin in rats. 409 81

The clinical effectiveness of conservative therapeutic modalities for hepatocellular carcinoma (HCC) was evaluated in terms of extension of survival. The therapeutic methods included one-shot therapy (OST) using Mitomycin C (MMC), Adriamycin (ADM), simultaneous ADM & MMC, with or without transcatheter arterial embolization (TAE). Prior to estimating the effectiveness, the subjects were graded into three stages according to the pretreatment severity of their residual liver function, based on total bilirubin, aspartate aminotransferase/alanine aminotransferase ratio, and ascites as constituent factors. OST with or without TAE significantly prolonged the mean survival time in stage I cases in good condition and in stage II cases in fair condition, but not in stage III cases in poor condition. Concerning OST without TAE, the results of ADM were slightly better than MMC in terms of extension of survival. OST combined with TAE was far more effective than OST without TAE. Extension of survival by simultaneous ADM & MMC is now under observation, but the toxicity of the modality has so far not proved serious. The long-term influence of repeated TAE on liver function was revealed to be mild within an average observation period of approximately one year. This study confirmed the validity of the present staging system in evaluating the efficacy of OST and TAE in terms of extension of survival.
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PMID:Evaluation of conservative therapeutic modalities for hepatocellular carcinoma--analysis of 206 cases. 609 97

As a novel method for the medical application of liposomes, we have tried hepatic artery chemoembolization using temperature-sensitive liposomes with hyperthermia for the treatment of hepatic tumors. In this study, the effect of temperature-sensitive liposomes was compared with that of Lipiodol emulsion, which has been used clinically. The temperature-sensitive liposomes, consisting of dipalmitoylphosphatidylcholine or Lipiodol emulsions entrapping doxorubicin, were administered into the hepatic artery of hepatic tumor-bearing rats via a cannula. Doxorubicin administered in a liposomal form showed a high accumulative property toward tumors, with heating, while that in the emulsion form showed a slow release property toward tumors. Not only was tumor growth inhibited, but also, an actual diminishing of the tumor was observed in each form. Side effects were also examined: an abnormal rise in GPT, or necrosis of the normal tissues in liver, which was often observed in hepatic artery chemoembolization using Lipiodol emulsion, was remarkably reduced in the liposomal chemoembolization.
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PMID:Study on hepatic artery chemoembolization using temperature-sensitive liposome or lipiodol emulsion. 774 98

Our working hypothesis states that DNA damage is a critical step in toxic cell death. The DNA hypothesis was tested in cultured mouse hepatocytes by examining whether inhibitors of DNA repair would increase dimethylnitrosamine toxicity and DNA damage in parallel. Inhibitors were chosen for selectivity toward DNA polymerase alpha (aphidicolin, myricetin), DNA ligase (ethidium bromide), or multiple repair enzymes (ara-C, doxorubicin). Dimethylnitrosamine caused concentration-dependent DNA damage at 6 hr and cell death at 24 hr (35% ALT release vs. 8.8% in control cultured hepatocytes). Each repair inhibitor increased dimethylnitrosamine-induced DNA damage and toxic cell death in parallel. Doxorubicin maximally elevated DNA fragmentation and toxicity (57% ALT release). Repair inhibitors alone failed to damage DNA or cause cell death in this model system. These data support the hypothesis that DNA damage is an early causal event in toxic cell death caused by alkylating hepatotoxicants.
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PMID:DNA as a critical target in toxic cell death: enhancement of dimethylnitrosamine cytotoxicity by DNA repair inhibitors. 799 86

Mammalian cells in culture have been used to study the genetic effects of physical and chemical agents. We have used Chinese hamster ovary (CHO) cells, clone K1-BH4, to quantify mutations at the X-linked, large (35 kb) hypoxanthine-guanine phosphoribosyltransferase (hprt) locus (the CHO/HPRT assay) induced by environmental agents. By transfecting an hprt-deletion mutant CHO cell line with the plasmid vector pSV2gpt, we isolated a transformant, AS52. AS52 cells carry a single functional copy of an autosomal, small (456 bp) xanthine-guanine phosphoribosyltransferase (gpt) gene (the bacterial equivalent of the mammalian hprt gene; AS52/GPT assay). We found that ionizing radiations such as X-rays and neutrons and oxidative genotoxic chemicals such as Adriamycin, bleomycin, hydrogen peroxide, and potassium superoxide are much more mutagenic to the gpt gene in AS52 cells than to the hprt locus in K1-BH4 cells. The hypermutability of the gpt gene probably results from a higher recovery of multilocus deletion mutants in AS52 cells than in K1-BH4 cells, rather than a higher yield of induced mutants. These results demonstrate that the use of the hprt locus alone could lead to an underestimate of the genetic risk of these agents. Analyses of the mutation spectrum using a polymerase chain reaction-based deletion screening and DNA sequencing procedure showed that a high proportion of HPRT- and GPT- mutants induced by X-rays carry deletion mutations. Thus, both the mutant frequency and mutation spectrum need to be considered in assessing the genetic risk of ionizing radiation and oxidative genotoxic chemicals.
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PMID:Quantitative and molecular analyses of genetic risk: a study with ionizing radiation. 814 20

Doxorubicin produces clinically useful responses in a variety of human cancers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin-mediated free radical formation. Administration of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme oxygenase-1 (HO-1) in the liver. The levels of HO-1 protein were first detected at 6 hours and peaked at about 18 to 24 hours after the injection. It is known that HO-1 plays a protective role against the oxidative injury. Therefore, we have examined the protective effect of doxorubicin preconditioning against the hepatic ischemia-reperfusion injury. Partial hepatic ischemia was produced in the left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in the preconditioning rat were clearly improved compared with those in the rat without preconditioning. Under this situation, zinc-protoporphyrin IX, a specific inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before the ischemia, the ALT levels were not improved by doxorubicin preconditioning. Histopathologic examination also supported these results. Although the HO-1 protein level was fairly low 2 days after the doxorubicin administration, significant amounts of HO-1 protein were detected. Our results indicated that the induction of HO-1 played a protective role against hepatic ischemia-reperfusion injury and that doxorubicin preconditioning is more clinically useful than other preconditioning methods.
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PMID:Doxorubicin preconditioning: a protection against rat hepatic ischemia-reperfusion injury. 1065 83

Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme into biliverdin, carbon monoxide, and iron. HO-1, an inducible form, is thought to contribute to resistance to various types of oxidative stress. Doxorubicin (DOX) produces clinically useful responses in a variety of human cancers. We reported previously that prior administration of DOX ameliorated subsequent hepatic ischemia and reperfusion injury. The aim of this study was to examine whether this pharmacological preconditioning was useful for another type of hepatic injury induced by a non-surgical method. When a high dose of DOX (10 mg/kg body weight) was administered directly to rat liver via the portal vein, serum aspartate transaminase (AST) and alanine transaminase (ALT) levels increased markedly 24 hr after the injection. Under this condition, zinc-protoporphyrin IX, a specific inhibitor of HO-1, caused both serum AST and ALT levels to be elevated further. When a low dose of DOX (5 mg/kg body weight) was administered to rats via the tail vein as pharmacological preconditioning 3 days before the injection of a high dose of DOX via the portal vein, the levels of serum AST and ALT in rats clearly were improved as compared with rats without the preconditioning. Expression of HO-1 in the liver was confirmed 3 days after the administration of a low dose of DOX. In addition, prior administration of zinc-protoporphyrin IX abolished the effect of DOX preconditioning. Immunohistochemical analysis showed that the positive staining of HO-1 protein induced by a low dose of DOX was localized to histiocytes infiltrating periportal areas. These results strongly suggest that pharmacological preconditioning with DOX may generally help to attenuate subsequent oxidant-induced hepatic injury.
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PMID:Pharmacological preconditioning with doxorubicin. Implications of heme oxygenase-1 induction in doxorubicin-induced hepatic injury in rats. 1170 58

Oleuropein (oleu) is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves. Doxorubicin (DXR) induced cardiotoxicity is mainly induced by oxidative stress but the precise mechanism remains obscure. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation may be involved in DXR cardiotoxicity. The aim of the present study was to evaluate a possible protective role of oleu in DXR induced cardiotoxicity in vivo. Fifty rats were divided into 6 groups and treated as follows: control group with a single injection of 2 ml normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg i.p, and DXR plus oleu groups with 20 mg/kg DXR i.p. and 100 or 200 mg/kg/BW of oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Seventy-two hours after DXR treatment blood samples were collected for creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) assessments and the rats were then sacrificed. Hearts were used for general histology, iNOS immunohistochemical and Western blot analysis, and for determination of tissue concentrations of lipid peroxidation products, protein carbonyls (PCs), and nitrotyrosine (NT). DXR treated animals demonstrated very extensive cytoplasmic vacuolisation whereas much less vacuolisation was found in oleu treated groups. They also revealed a significant elevation of cardiac enzymes release into systemic circulation (P<0.05 vs saline). Both doses of Oleu tested and both treatment protocols reduced DXR elevated serum levels of CPK, CPK-MB, LDH, AST and ALT (P<0.05). Furthermore, it reduced DXR induced lipid peroxidation, PCs content, NT concentration and iNOS induction in myocardial tissue (P<0.05). Oleu exerts a protective effect by eliminating DXR induced cardiotoxicity expressed by the alteration of intracellular and peripheral markers. Combined oleu and DXR treatment improves the therapeutic outcome by preventing undesirable toxicity.
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PMID:Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress. 1722 28

1. Doxorubicin is an anti-cancer drug with well-described effects against a wide range of tumours. However, doxorubicin also exhibits dose-dependent cytotoxicity. The purpose of the present study was to determine whether chronic supplementation of creatine or a mix of vitamins C and E could increase survival and improve plasma parameters 48 h after doxorubicin treatment. 2. Rats were divided into four groups: (i) saline (control); (ii) doxorubicin treated; (iii) a creatine (0.2 g/kg per day)-supplemented group; and (iv) a vitamin C (250 mg/kg per day) and E (400 IU/kg per day)-supplemented group. After 30 days supplementation of rats with either creatine or the vitamins, one dose of doxorubicin (15 mg/kg, i.p.) was administered. 3. There was no difference in weight loss among the groups until the 3rd day after doxorubicin treatment, but the creatine- and vitamin-supplemented groups lived longer compared with the doxorubicin only treated group (6, 7 and 3 days, respectively). The doxorubicin-treated group lost 13.4% bodyweight over 3 days, whereas the creatine- and vitamin-supplemented groups lost approximately 35% 3 days after the administration of doxorubicin. Doxorubicin treatment resulted in an increase in alanine aminotransferase (ALT; P < 0.05), lactate dehydrogenase (LDH; P < 0.05), urea (P < 0.05) and creatinine (P < 0.05) compared with levels observed in the control group. Conversely, creatine supplementation promoted a partial return to control values for LDH (P < 0.05) and creatinine (P < 0.05), whereas the vitamin mix reversed the changes in ALT (P < 0.05), LDH (P < 0.05), urea (P < 0.05) and creatinine (P < 0.05). 4. In conclusion, the results of the present study indicate that the two supplementation protocols decreased the cytotoxic effects of doxorubicin and that a protective effect was more noticeable in animals supplemented with the mixture of vitamins C and E.
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PMID:Chronic supplementation of creatine and vitamins C and E increases survival and improves biochemical parameters after Doxorubicin treatment in rats. 1797 71


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