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 influence of 5,10-dihydroindeno[1,2-b]indole (indenoindole) on carbon tetrachloride (CCl4)-mediated hepatotoxicity and lipid peroxidation were examined. Indenoindole (25 mg/kg body weight) ameliorated the increase in liver enzymes appearing in the plasma 24 hr after CCl4 administration, with about a 63% reduction for alanine transaminase, 56% for ornithine transcarbamylase and 84% for alkaline phosphatase. Indenoindole also partially prevented, in a dose-dependent fashion, the decrease in hepatic cytochromes P-450, total tissue reducing equivalents and hepatic ascorbate levels resulting 4 hr after CCl4 administration. In a homogeneous chemical system consisting of purified soybean phospholipid substrate in chlorobenzene, azobisisobutyronitrile-initiated lipid peroxidation was inhibited by indeno-indole, with 50% inhibition occurring at about 17 microM. Inhibition by indenoindole of iron-ascorbate-initiated lipid peroxidation in aqueous buffer containing phospholipid vesicles was about tenfold more efficient, with 50% inhibition occurring at about 1.5 microM. Presumably, this was due to the increased concentration of indenoindole in the membrane of the phospholipid vesicle. The efficiency of inhibition of lipid peroxidation was in the order of indenoindole = butylated hydroxytoluene (BHT) greater than alpha-tocopherol much greater than indole greater than indene. These 50% inhibition values of lipid peroxidation for these compounds were similar in an assay system composed of NADPH-fortified mouse-liver microsomes initiated with CCl4. For indenoindole, the 50% inhibition value (1.3 microM) was more than two orders of magnitude less than the spectral binding constant for indenoindole to mouse-liver cytochrome P-450 (Kd = 236 microM), implying that the partial inhibition of metabolic activation of CCl4 was not responsible for the inhibition of lipid peroxidation observed with indenoindole in this system. It appears that indenoindole may trap reactive radicals and inhibit lipid peroxidation in vitro. Regardless of whether inhibition is at the level of scavenging CCl4 metabolite radicals, or lipid radicals in membranes, radical trapping provides a plausible mechanism by which this compound inhibited CCl4 hepatotoxicity.
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PMID:Protection against carbon tetrachloride hepatotoxicity by 5,10-dihydroindeno[1,2-b]indole, a potent inhibitor of lipid peroxidation. 316 51

An investigation was carried out to evaluate the ability of Melothria maderaspatana to protect the livers of albino rats from carbon tetrachloride-mediated alterations in liver histopathology and serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Treatment with an aqueous extract of Melothria aerial parts (either before or after CCl4 administration) markedly decreased CCl4-mediated alterations in liver histopathology as well as serum enzyme levels. Results provide supportive evidence for the folklore view that this plant is a good hepatotonic.
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PMID:Evaluation of the efficacy of Melothria maderaspatana in the alleviation of carbon tetrachloride-induced liver dysfunction. 319 93

Pharmacological studies on trithio-p-methoxy-phenylpropene (anethole trithione, ANTT, Felviten) were performed. ANTT at a dose of 100 mg/kg, p.o. lowered the increased serum transaminases GOT and GPT, and protected the liver from injuries caused by CCl4 in mice. In other studies in vivo, ANTT at a dose of 1000 mg/kg showed no effect on the central nervous system or the autonomic nervous system. In vitro experiments with smooth muscle preparations showed no significant effects of ANTT.
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PMID:Pharmacological studies on anethole trithione. 319 85

Carbon tetrachloride-mediated hepatotoxicity in mice was influenced by two standard, commercially available diets and by a corn oil treatment vehicle. Animals maintained on Purina 5001 diet were less sensitive than animals maintained on Teklad LM-485 diet to hepatic intoxication by carbon tetrachloride (CCl4). Lower sensitivity of the Purina group was evidenced by significantly lower plasma alanine aminotransferase (ALT) levels and higher hepatic cytochrome P-450 levels at all dosages of CCl4. In addition to the diets, the nature of the corn oil vehicle affected toxicological responses of mice to CCl4. When the vehicle from which tocopherols had been extracted was used, CCl4 elicited about twice the levels of plasma ALT than when nonextracted corn oil was used. In conclusion, the nature of the animal diet and treatment vehicle not only can influence toxicological response, but also can be important considerations in the interpretation of toxicological data.
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PMID:Influence of diet on the expression of hepatotoxicity from carbon tetrachloride in ICR mice. 324 Jul 10

The cytoprotective effect of the natural dietary constituent indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4) mediated hepatotoxicity in mice was examined. I-3-C pretreatment by gavage 1 hr prior to intraperitoneal injection of CCl4 produced a 63% decrease in CCl4-mediated centrolobular necrosis and a related 60% decrease in plasma alanine aminotransferase activity (a marker of liver necrosis). Since the toxicological effects of CCl4 are mediated by radical species generated during reductive metabolism by cytochrome P-450, we examined the potential ability of I-3-C to scavenge reactive radicals. Three systems were used to evaluate the ability of I-3-C to intervene in free radical mediated lipid peroxidation. These systems consisted of the following: (1) phospholipid dissolved in chlorobenzene, with peroxidation initiated by the thermal and photo decomposition of azobisisobutyronitrile (AIBN); (2) sonicated phospholipid vesicles in phosphate buffer (pH 7.4), with peroxidation initiated by ferrous/ascorbate; and (3) mouse liver microsomes containing an NADPH-regenerating system, with peroxidation initiated with CCl4. Lipid peroxidation was measured in these three systems as thiobarbiturate-reacting material. In the AIBN and ferrous/ascorbate systems, I-3-C inhibited lipid peroxidation, with greater inhibition under conditions of low rates of free radical generation. I-3-C was not as effective an antioxidant as butylated hydroxytoluene (BHT) or tocopherol, but it inhibited peroxidation in a dose-response manner. I-3-C was most effective as a radical scavenger in the microsomal CCl4-initiated system by inhibiting lipid peroxidation in a dose-dependent fashion, with 50% inhibition at 35-40 microM I-3-C. This concentration is about one-third of the concentration of I-3-C achieved in liver after treatment of mice by gavage with 50 mg I-3-C/kg body weight. These data suggest that I-3-C may be a natural antioxidant in the human diet and, as such, may intervene in toxicological or carcinogenic processes that are mediated by radical mechanisms.
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PMID:Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol. 334 90

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.
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PMID:The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats. 335 67

The effects of hypothalamic stimulation on experimental liver injury induced by carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN) were studied in rats, by measuring plasma alanine aminotransferase (ALT) activity as an index of acute liver injury. Electrical stimulation of the ventromedial hypothalamus (VMH) in CCl4-treated rats caused a marked increase in plasma ALT activity, accompanied by a significant decrease in ALT activity in the liver, although CCl4 treatment alone had no significant effect on plasma ALT activity. A similar effect of VMH stimulation on plasma ALT activity was observed in rats treated with DMN, another hepatotoxic chemical. No such exaggerated effect of VMH stimulation on plasma ALT activity was observed after stimulation of the lateral hypothalamic area (LH). Surgical sympathetic denervation of the liver greatly suppressed the increase in plasma ALT activity after CCl4 injection and VMH stimulation. Measurement of regional blood flow indicated that VMH stimulation did not produce a significant change in blood flow to the liver. These results suggest that the VMH is involved in the progress of chemically-induced liver injury through activation of the sympathetic nerve (hepatic nerves), possibly by affecting liver metabolism more than the blood flow change to the liver.
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PMID:Effects of ventromedial and lateral hypothalamic stimulation on chemically-induced liver injury in rats. 336 88

Administration of acetone to rats in amounts larger than or equal to a minimal effective dosage (MED) is known to potentiate the severity of the liver damage produced by CCl4 alone. It has been reported that CCl4-induced hepatotoxicity is also enhanced by the previous administration of trichloroethylene (TCE). In addition, TCE-CCl4 mixture-induced liver injury is potentiated by acetone. The present study was undertaken to determine if the acetone MED is decreased when the haloalkane challenge is a mixture of TCE-CCl4 instead of CCl4 alone. The effect of varying mixture compositions was also evaluated. In a first series of experiments, male Sprague-Dawley rats received corn oil or acetone (0.05-0.25 ml/kg, po); 18 hr later, they received an ip injection of either CCl4 (0.1 ml/kg) or [TCE (0.25 ml/kg)-CCl4 (0.1 ml/kg)]. In a second series, rats received corn oil or acetone (0.75 ml/kg), and were challenged with TCE (1.5 ml/kg), CCl4 (0.25 ml/kg), or a mixture of TCE-CCl4, where TCE and CCl4 dosages were equal to 25-75%, 50-50%, and 75-25%, respectively, of those used for the administration of the solvents alone. In both series, rats were killed 24 hr after the haloalkane challenge. Liver injury was assessed biochemically (plasma ALT activities and bilirubin concentrations) and morphologically. When TCE was added to a solution of CCl4, smaller doses of CCl4 were required to produce equally severe liver injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of the minimal effective dose of acetone for potentiation of the hepatotoxicity induced by trichloroethylene-carbon tetrachloride mixtures. 337 82

To study the relationship between the changes in hepatocytes and calcium contents in the liver of 42 rats treated with CCl4 and the effect of a calcium antagonist diltiazem on the liver injury, we determined liver calcium content, serum alanine aminotransferase (ALT), and serum levels of triiodothyronine (T3), thyroxine (T4), the T3/T4 ratio, and calcium before and 6 to 72 hr after treatment with a single oral dose of CCl4 (0.5 ml/kg) in 21 rats (Group I) and in 21 rats treated with diltiazem (10 mg/kg) intraperitoneally three times, 24 hr before, simultaneously with, and 24 hr after administration of the same doses of CCl4 (Group II). The maximum calcium content in Group I was 259.7 +/- 53.3 micrograms/g wet weight at 24 hr after treatment, whereas it was 113.0 +/- 51.1 micrograms/g wet weight in Group II, and a significant difference was seen between them (p less than 0.05). The ALT levels in both groups elevated after 18 to 24 hr and a significant difference was also found between the two levels at 24 hr (p less than 0.05). The T3/T4 ratio in Group I decreased immediately, but increased later. The ratio in Group II maintained the level before treatment. Correlation between the calcium content and the grade of centrilobular necrosis was significantly seen in Group I (r = 0.82, p less than 0.001), but was not found in Group II. The grade of centrilobular necrosis appeared to be more severe at 24 to 48 hr in Group I than in Group II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of calcium antagonist diltiazem on liver calcium content and necrosis of hepatocytes in rats following treatment with CCL4. 338 Oct 7

Potentiation of haloalkane hepatotoxicity by ketones and ketogenic agents is a well-known phenomenon. The importance of the CCl4 dosage in these combinations, however, has not been explored. Its influence was investigated in male Sprague-Dawley rats. Dose-effect curves for potentiation were generated using 1,3-butanediol, methyl n-butyl ketone or methyl isobutyl ketone as potentiation agents. Animals were orally treated with these compounds prior to a challenge of CCl4 (0 to 0.5 ml/kg, ip). Liver injury was assessed by monitoring plasma ALT activity and bilirubin concentrations after CCl4 treatment. The minimal effective dosage (MED) for each potentiator was used as the criterion of comparison for each combination. The MED values were determined from the plasma ALT data. Results showed that when the CCl4 dosage was increased from 0.01 to 0.10 ml/kg, the MED of each potentiator decreased 10-fold. For a given potentiator, the product of the CCl4 dosage (H, "hepatotoxicant") by the corresponding MED value (P, "potentiator") remained the same in this range of CCL4 dosages. The severity of the liver injury was similar. These findings suggest that a given level of liver injury induced by a ketone/haloalkane combination could be evaluated on the basis of the [P X H] product.
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PMID:Potentiation of CCl4-induced liver injury by ketonic and ketogenic compounds: role of the CCl4 dose. 338 17


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