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

---

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

The morphological and biochemical studies were performed on the injured livers of female rats produced by chronic administration of D-galactosamine (GALN) (250 mg/kg, i.p.) for 7 months. Light microscopically, cirrhotic changes were observed in most of the animals characterized by the proliferation of the connective tissues from portal triads into hepatic lobules. The electron microscopic study demonstrated mitochondrial proliferation and irregularities with crenated membranes, focal hypertrophy of the smooth endoplasmic reticulum, decrease of the rough endoplasmic reticulum with partial detouchment of ribosomes, slight loss of compactness of nucleoli and no remarkable accumulation of lipid droplets in the cytoplasm. The proliferation of collagen fibers was observed around the hepatocytes and acid mucopolysaccharides were seen in the space of Disse and partly in the sinusoids histochemically using electron microscope. Biochemically chronic GALN administration, which increased hepatic weight significantly, resulted in a significant decrease in microsomal protein concentration, whereas cytochrome P450 content significantly increased. There was no change in phospholipid contents. After GALN, plasma albumin concentration was significantly decreased and the value of zinc turbidity test was increased. However, there was no change in plasma GPT level and total cholesterol concentration.
...
PMID:D-galactosamine induced hepatic cirrhosis: its ultrastructural and biochemical studies in rat. 65 50

The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho-DCB (o-DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three endpoints, meta-DCB (m-DCB) exhibited a lesser toxicity. Para-DCB (p-DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m-DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p-DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o-DCB and p-DCB were administered at dosages several times the oral rat LD-50 (RTECS) without any lethality.
...
PMID:The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene. 129 13

Acetaminophen is eliminated primarily by glucuronidation, thereby avoiding cytochrome P450-catalyzed bioactivation to a toxic reactive intermediate. Previous studies have shown that UDP-glucuronosyltransferase-deficient Gunn rats are more susceptible to acetaminophen toxicity than normal Wistar controls, from which the Gunn strain was derived. However, the Gunn and Wistar strains are not congenic, and differences in toxicologic susceptibility could be due in part to genetic differences other than UDP-glucuronosyltransferase activity. Accordingly, acetaminophen (750 mg/kg, ip) was administered to congenic RHA rats with normal (homozygous, RHA/++), moderately deficient (heterozygous, RHA/j+), and severely deficient (homozygous jaundiced, RHA/jj) activities of bilirubin UDP-glucuronosyltransferase. Acetaminophen metabolites were measured by high-performance liquid chromatography and production of the acetaminophen glucuronide conjugate was quantified by the area under plasma concentration-time curve (AUC) from 0 to 2 hr, standardized by the AUC value for acetaminophen in the same animal (glucuronidation ratio = AUC acetaminophen glucuronide/AUC acetaminophen). The 0- to 2-hr time period for AUC calculations was necessitated by the accumulation at later time points of glucuronide and sulfate conjugates in the plasma of animals experiencing severe nephrotoxicity. Acetaminophen bioactivation was quantified by the 24-hr urinary recovery of glutathione-derived conjugates. Hepatotoxicity and nephrotoxicity were assessed respectively by the peak concentrations of plasma alanine aminotransferase (ALT) and blood urea nitrogen (BUN). Glucuronidation of acetaminophen in RHA/jj rats (0.065 +/- 0.005) (mean +/- SE) was reduced 63% compared to the RHA/++ controls (0.17 +/- 0.01) (p < 0.05). RHA/jj rats demonstrated respective 230- and 7-fold increases in the peak plasma concentrations of ALT (17144 +/- 1014 vs 75 +/- 10) and BUN (128 +/- 23 vs 18.4 +/- 0.2) compared to congenic normal controls (RHA/++) (p < 0.05). Heterozygous animals (RHA/j+) demonstrated intermediary toxicity for both parameters (ALT = 2029 +/- 1581, BUN = 41 +/- 16, p < 0.05). Decreased glucuronide production correlated with elevations in ALT (r = -0.86, p < 0.001), while increased acetaminophen bioactivation correlated directly with both elevated ALT (r = 0.93, p < 0.001) and BUN (r = 0.83, p = 0.001). These results using congenic controls demonstrate that the enhanced susceptibility of UDP-glucuronosyltransferase-deficient rats to acetaminophen toxicity is due to decreased glucuronidation resulting in enhanced bioactivation, rather than to other unappreciated genetic differences.
...
PMID:Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase. 144 Jun 17

The effects of modulators of cytochrome P450 and reduced glutathione (GSH) on the hepatotoxicity of enalapril maleate (EN) were investigated in Fischer 344 rats. Twenty-four hours following the administration of EN (1.5 to 1.8 g/kg), increased serum transaminases (ALT and AST) and hepatic necrosis were observed. Pretreatment of the animals with pregnenolone-16 alpha-carbonitrile, a selective inducer of the cytochrome P450IIIA gene subfamily, enhanced EN-induced hepatotoxicity, whereas pretreatment with the cytochrome P450 inhibitor, cobalt protoporphyrin, reduced the liver injury. Depletion of hepatic non-protein sulfhydryls (NPSHs), an indicator of GSH, by combined treatment with buthionine sulfoximine (BSO) and diethyl maleate (DEM) produced marked elevations in serum transaminases by 6 hr after EN treatment. Administered on its own, EN decreased hepatic NPSH content and when combined with the BSO/DEM pretreatment, the liver was nearly completely devoid of NPSHs. Protection from EN-induced hepatotoxicity was observed in animals administered L-2-oxothiazolidine-4-carboxylic acid, a cysteine precursor. Together, these observations suggest the involvement of cytochrome P450 in EN bioactivation and GSH in detoxification. The results corroborate previous in vitro observations pertaining to the mechanism of EN-induced cytotoxicity towards primary cultures of rat hepatocytes. Although the doses of EN used in this study were far in excess of therapeutic doses, under certain circumstances, this metabolism-mediated toxicologic mechanism could form the basis for idiosyncratic liver injury in patients receiving EN therapy.
...
PMID:Enalapril hepatotoxicity in the rat. Effects of modulators of cytochrome P450 and glutathione. 144 35

Exposure of cultured primary hepatocytes from Ah-responsive male C57BL/10ScSn mice to a polychlorinated biphenyl (PCB) mixture (Aroclor 1254) at 0.1-20 micrograms/mL for up to 96 hr induced cytochrome P4501AI-mediated activity (ethoxyresorufin O-deethylase, EROD) up to 50-fold. In contrast, pentoxyresorufin O-dealkylase (PROD), which in some circumstances is a measure of phenobarbitone-induced cytochrome P450 isoenzymes, was induced only 5-fold. There were similar findings on EROD activities with the pure compounds 3,3',4,4',5,5'-hexachlorobiphenyl, 3,3',4,4',5,5'-hexabromobiphenyl and 3,3',4,4'-tetrachlorobiphenyl(TCB) and also beta-naphthoflavone but not with 2,2',4,4'-TCB or phenobarbitone. The higher concentrations of Aroclor 1254 were also associated with cytotoxicity as estimated by release of alanine aminotransferase (ALT) into the medium. Unlike in C57BL/10ScSn hepatocytes induction of EROD and cytotoxicity was minimal in hepatocytes from the Ah-non-responsive strain DBA/2. Although in vivo the hepatic toxicity and carcinogenicity of polyhalogenated aromatics are markedly potentiated by iron, no enhancement of the cytotoxicity of Aroclor 1254 towards C57BL/10ScSn hepatocytes by iron was observed in vitro. However, iron caused decreased EROD activities and possibly cytochrome P4501AI (as judged by Western blotting) as in vivo. Even in the presence of iron and the haem precursor 5-aminolaevulinic acid (5-ALA) there was no development of uroporphyria in this system although this occurs with Aroclor in vivo and is enhanced by iron. Accumulation of uroporphyrin did occur after extended culture of C57BL/10ScSn hepatocytes on matrigel for 8 days in the presence of 5-ALA and Aroclor 1254 but again no potentiation by iron was observed. Thus, although culture of Ah-responsive and -non-responsive hepatocytes mimics some aspects of the mechanisms of in vivo toxicity of PCBs, there is some unknown associated influence of iron metabolism which cannot, as yet, be produced in vitro but which is of importance in vivo.
...
PMID:Induction of cytochrome P450 activities by polychlorinated biphenyls in isolated mouse hepatocytes. Influence of Ah-phenotype and iron. 151 Jun 96

Previous studies have shown that dichloroacetate and trichloroacetate increase the toxicity of CHCl3. The present experiments were designed to determine if monochloroacetate (MCA) similarly affects CHCl3 toxicity. There were occasional differences, but overall kidney function indices (urine volume, osmolality and electrolyte concentration, glucosuria, retention of urea nitrogen in plasma) were not affected differently at either 24 or 48 hr after CHCl3 in saline and MCA pretreated Sprague-Dawley rats of either sex. Males pretreated with MCA had 45-fold greater plasma alanine aminotransferase (ALT) compared to the saline pretreated group similarly dosed with CHCl3. ALT was increased threefold in female rats, a modest change that suggests hepatic damage, and BUN was nonsignificantly increased. Therefore hepatic and renal functions were assessed in females. MCA pretreatment did not alter the effects of CHCl3 on hepatic excretory function or glomerular or tubular function. Bile production and glomerular filtration were both decreased in the MCA group treated with peanut oil, suggesting that MCA impairs both liver and kidney function in female rats. MCA pretreatment increases CHCl3 hepatoxicity markedly in male rats and only slightly in female rats. This difference is likely due to the different effects, in males and females, of MCA on the cytochrome P450 isoforms that activate CHCl3. The effects of MCA on renal function in females would decrease CHCl3 delivery to kidney cells, suggesting that MCA may alter the distribution of CHCl3.
...
PMID:Sex differences in monochloroacetate pretreatment effects on chloroform toxicity in rats. 160 Dec 11

We report the development of severe hepatotoxicity in a patient on zidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient's serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 mumol/L. These values substantially improved over the ensuing 4 days. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus were all negative. The pattern and time sequence of transaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since zidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesize that our patient's susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as zidovudine and/or trimethoprim-sulfamethoxazole with subsequent increased cytochrome P450-dependent metabolism of acetaminophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the P450 system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving zidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when taking both these medications.
...
PMID:Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. 836 34

The immunotoxicity, hepatotoxicity, and nephrotoxicity of subacute exposure to carbon tetrachloride (CCl4) were evaluated in young adult (8-9 weeks old) male Fischer 344 rats dosed by gavage with CCl4 for 10 consecutive days at 0, 5, 10, 20 or 40 mg/kg/day. Two days following the last treatment rats were evaluated for alterations in immune function by monitoring the following: body and lymphoid organ weights; mitogen and mixed leukocyte reaction lymphoproliferative responses; natural killer cell activity; and cytotoxic T lymphocyte responses. A separate group of similarly dosed rats was immunized with sheep red blood cells (SRBC) on Day 9 of dosing, and the primary antibody response was assessed 4 days later. Hepatic and renal toxicity were assessed 2 days after the last treatment by monitoring organ weights, serum indicators of hepatic and renal damage, and hepatic cytochrome P450 levels, as well as by histological evaluation. Significant increases in relative liver weights were observed in rats dosed at 40 mg/kg/day. Histologically, these livers displayed mild to moderate vacuolar degeneration and minimal to mild hepatocellular necrosis. In addition, serum levels of aspartate aminotransferase and alanine aminotransferase were elevated at this dosage, as well as at 20 mg/kg/day. There were no renal effects observed at these dosages of CCl4. In addition, no consistent alterations were observed in the immune parameters examined in these same animals nor in the rats immunized with SRBC. Furthermore, there was no difference in the antibody response to SRBC in another set of rats dosed at 40, 80 or 160 mg/kg/day CCl4. These results indicate that CCl4 is not immunotoxic in the rat at dosages that produce overt hepatotoxicity.
...
PMID:Immunotoxicologic assessment of subacute exposure of rats to carbon tetrachloride with comparison to hepatotoxicity and nephrotoxicity. 183 55

The present investigation was undertaken to test our hypothesis that the slow responses of hepatocellular regeneration and tissue repair after CCl4-induced liver injury are responsible for the high sensitivity of gerbils to the hepatotoxic and lethal effects of CCl4. These studies were conducted in normal and actively regenerating livers using male gerbils 5 or 15 days after partial (2/3) hepatectomy (PH5 and PH15, respectively), or those undergoing sham operation (SH). An LD50 dose of CCl4 (80 microL/kg, i.p.) resulted in a mortality (21%) significantly (P less than 0.05) less than 50% in PH5 gerbils 48 hr after CCl4 administration, whereas the mortality observed in PH15 or SH gerbils was not significantly different from 50%. The elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly (P less than 0.05) less in PH5 gerbils than in PH15 or SH groups after the administration of either the LD50 dose or a low dose (15 microL/kg) of CCl4. Histopathological and histomorphometric examinations also indicated that CCl4-induced liver injury was less severe in PH5 gerbils than in the PH15 and SH groups. The hepatic microsomal cytochrome P450 content measured before CCl4 administration in the PH5 gerbils was decreased (26%) significantly (P less than 0.05) as compared with the SH group, but was not significantly different from that of PH15 gerbils. In vivo metabolism of 14CCl4 and lipid peroxidation in liver tissue were not significantly different among the various groups. Therefore, the protection against CCl4 toxicity observed in PH5 gerbils is unlikely to be due to decreased bioactivation of CCl4 or lipid peroxidation in that group. [3H]Thymidine incorporation into hepatocellular nuclear DNA was 4- to 5-fold higher in PH5 gerbils than in the PH15 and SH groups, indicating active hepatocellular proliferation in PH5 gerbils. [3H]Thymidine incorporation was further increased significantly (P less than 0.05) 24 hr after challenge with a low dose of CCl4 in PH5 gerbils, whereas it remained low until 48 hr after the CCl4 injection in the PH15 or SH group. The protection against CCl4 toxicity afforded by partial hepatectomy was closely associated with active hepatocellular regeneration. The overall results confirm the concept that the high sensitivity of gerbils to CCl4 is due to very sluggish hepatocellular regeneration and tissue repair response to the CCl4-induced liver injury.
...
PMID:Protection from CCl4 toxicity by prestimulation of hepatocellular regeneration in partially hepatectomized gerbils. 185 67

In the companion paper we demonstrated that hepatic vitamin E in rats becomes depleted and extrahepatic pools of vitamin E are altered by treatment with 1,2-dibromoethane (DBE). Vitamin E depletion may be dependent upon initial steps of DBE metabolism that are either oxidative (cytochrome P450 dependent) or conjugative (glutathione transferase dependent). That the liver content of glutathione (GSH) and vitamin E, the plasma concentration of vitamin E, and the serum activities of AST and ALT may be influenced by cytosolic metabolism of DBE was assessed by comparison of findings from rats treated with either 1,2-dichloroethane (DCE) or 1-bromo-2-chloroethane (BCE). The extent of oxidative metabolism was diminished by the use of tetradeutero-DBE (d4-DBE), and the availability of GSH for conjugative metabolism was diminished by pretreatment of rats with L-buthionine-S,R-sulfoximine (BSO) prior to treatment with DBE. Our results indicate that neither DCE nor BCE provokes a liver vitamin E depletion in rats, that d4-DBE treatment hastens but does not enhance the observed hepatic vitamin E depletion by comparison to animals treated with an equimolar dose of DBE, and that BSO pretreatment prevented the hepatic vitamin E depletion observed from animals treated with DBE alone. These results indicate that hepatic vitamin E depletion is the unique sequelae to conjugation of GSH with DBE, and we suggest the reactive episulfonium ion intermediate or a macromolecular adduct of this ion derived from DBE may play a role in liver vitamin E depletion associated with exposure to DBE.
...
PMID:Modification of hepatic vitamin E stores in vivo. III. Vitamin E depletion by 1,2-dibromoethane may be related to initial conjugation with glutathione. 189 41


1 2 3 4 5 6 7 8 9 10 Next >>

---