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)

Acetaminophen hepatotoxicity is associated with its biotransformation to the reactive metabolite N-acetyl-p-benzoquinone imine that binds to protein. Two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated as primarily responsible for the bioactivation. To determine the relative contributions of these P450's, overnight fasted male NMRI mice were pretreated with 10 ml of 50% v/w propylene glycol/kg or fluvoxamine (10 mg/kg) at -80 and -20 min. relative to acetaminophen dosing to inhibit CYP2E1 and CYP1A2, respectively. Mice were sacrificed at 0.5 or 4 hr after a hepatotoxic dose of acetaminophen (300 mg/kg). Propylene glycol or propylene glycol plus fluvoxamine, but not fluvoxamine alone protected against acetaminophen hepatotoxicity as indicated by abolished increase in serum alanine aminotransferase activity, less depletion of hepatic glutathione and lower liver:body weight ratios. Propylene glycol inhibited the activity of CYP2E1 as indicated by 84% reduction in the clearance of 3 mg/kg dose of chlorzoxazone, whereas fluvoxamine inhibited the activity of CYP1A2 as indicated by 40% reduction in the clearance of a 10 mg/kg dose of caffeine. For this animal model, the data are consistent with the notion that hepatoxicity is associated with bioactivation of acetaminophen by CYP2E1 but not by CYP1A2.
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PMID:Cytochrome P4502E1 inhibition by propylene glycol prevents acetaminophen (paracetamol) hepatotoxicity in mice without cytochrome P4501A2 inhibition. 747 82

The contribution of cytochrome P450 isozymes CYP2E1 and CYP2B1/2 to chloroform-induced hepatotoxicity taken at 18 hr after the treatment was investigated in rats treated with n-hexane as an inducer of CYP2E1, 2-hexanone as an inducer of CYP2E1 and CYP2B1/2, and phenobarbital (PB) as an inducer of CYP2B1/2. Hepatic damage was evaluated by gross measurement of plasma alanine aminotransferase activity and histopathological examination. All treatments potentiated chloroform-induced hepatic damage. In n-hexane-pretreated rats, the damage was maximal with the middle dose of chloroform (0.2 ml/kg), whereas the damage increased with dose in rats treated with 2-hexanone or PB. The degree of hepatic damage induced with the three pretreatments was in the following order: n-hexane > 2-hexanone = PB with the middle dose of chloroform and PB >> 2-hexanone > n-hexane with the high dose (0.5 ml/kg); little difference among the pretreatments was seen with the low dose (0.1 ml/kg). These findings suggest that CYP2E1 is a low Km isoform and CYP2B1/2 a high Km isoform for chloroform activation. CYP2E1-dependent hepatic damage was characterized by ballooned hepatocytes, which were restricted to the centrilobular area; with CYP2B1/2, more necrotic than ballooned hepatocytes were seen and the necrotic hepatocytes were found not only in the centrilobular but also in the midzonal and periportal areas. Chloroform treatment did not affect the activity of N-nitrosodimethylamine N-demethylase in pretreated rats; the high dose increased the activity in control rats. In contrast, the high dose of chloroform decreased the activity of 7-pentoxyresorufin O-depentylase in all induced rats but not in controls. Immunoinhibition and immunoblot analyses showed that the high dose of chloroform induced CYP2E1 in control rats but decreased CYP2B1/2 in all pretreated rats. These results suggest that although both CYP2E1 and CYP2B1/2 contribute to chloroform-induced hepatic damage, they do so quite differently.
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PMID:Different contributions of cytochrome P450 2E1 and P450 2B1/2 to chloroform hepatotoxicity in rat. 764 16

Evidence suggests that 7 days of retinol pretreatment potentiates chemical-induced liver injury by a mechanism that involves activation of Kupffer cells (KC). These studies were designed to determine if shorter dosing regimens of retinol potentiate carbon tetrachloride (CCl4). Initially, a single dose of retinol was shown to potentiate the hepatotoxicity of CCl4. Male Sprague-Dawley rats were pretreated with all-trans-retinol (75 mg/kg p.o.) 24 hr prior to KC isolation or administration of CCl4 (0.2 ml/kg i.p.). KC isolated at 24 hr after retinol released increased amounts of superoxide anion when stimulated with zymosan or phorbol myristate acetate. At 24 hr after CCl4, plasma ALT activities and histological sections of liver were examined. Retinol-pretreated rats showed a significant elevation in both enzyme leakage and centrilobular to midzonal necrosis compared to retinol vehicle controls following CCl4. Although complete protection was not seen, depletion of KC or neutrophils (PMNs) (by gadolinium chloride (GdCl3) or a PMN-depleting antibody, respectively) significantly reduced the hepatotoxicity of 1 day retinol/CCl4 liver injury. Immunohistochemical analysis of livers showed significant elevations in positive staining for ED2, ED1, and HIS48 in retinol-pretreated rats given CCl4. GdCl3 effectively reduced ED2 staining but did not greatly affect HIS48 staining. Additional studies were performed to estimate the effect of retinol on noninflammatory processes. While total cytochrome P450 was not increased, the activity and concentration of CYP2E1 were both significantly elevated after a single dose of retinol. Hepatocytes isolated from 1-day retinol-treated rats were also more susceptible to CCl4 injury, a consequence that is most likely related to elevated CYP2E1 activity. These findings suggest that a single pretreatment with retinol may potentiate CCl4 hepatotoxicity by multiple mechanisms which involve increased biotransformation and inflammatory cell activities.
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PMID:The role of inflammatory cells and cytochrome P450 in the potentiation of CCl4-induced liver injury by a single dose of retinol. 897 75

The relationship was investigated between biochemical and morphological changes in chloroform (CHCl3)- and carbon tetrachloride (CCl4)-induced liver damage. The time courses of hepatic microsomal cytochrome P450 (CYP) content, hepatic microsomal CYP2E1 activity, hepatic reduced glutathione (GSH) content, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were examined in relation to the liver morphology in rats orally treated with CHCl3 or CCl4 (3.35 mmol/kg). The CYP content and the activity of CYP2E1 markedly decreased in the CCl4-treated rats 3 h after treatment compared to much lower decreases in the CHCl3-treated rats. The hepatic GSH content was decreased to a similar extent in both groups of rats at 3 h after treatment; in the CCl4-treated rats, the GSH content continued to decrease, reaching a minimum at 24 h and without attaining the normal level at 72 h after treatment. By contrast, hepatic GSH content in the CHCl3-treated rats began to increase from 6 h, attaining complete recovery 48 h after treatment. Plasma ALT and AST activities were significantly elevated by CCl4 as early as 3 h after treatment, while the activities in the CHCl3-treated rats did not increase until 6 h after treatment. In both groups of rats, ALT and AST activities reached a maximum at 24 h, and gradually decreased, remaining at abnormal levels at 72 h. Hepatic cells in the CCl4-treated rats were found to be necrotic as early as 3 h post-treatment, whereas few or no morphological changes appeared in the liver of CHCl3-treated rats. The extent of necrosis was at a maximum 24 h after treatment in both CHCl3- and CCl4-treated rats. In addition, some necrotic cells remained in the liver of CCl4-treated rats 72 h after treatment, while the necrosis in the CHCl3-treated rats was almost negligible. The present results indicate that almost the same time-courses of biochemical and morphological changes were followed in rats of both the CHCl3- and CCl4-treated groups.
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PMID:Time courses of hepatic injuries induced by chloroform and by carbon tetrachloride: comparison of biochemical and histopathological changes. 933 1

Acetaminophen (APAP) hepatotoxicity is due to its biotransformation to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), that is capable of binding to cellular macromolecules. At least two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated in this reaction in mice. To test the combined roles of CYP1A2 and CYP2E1 in an intact animal model, a double-null mouse line lacking functional expression of CYP1A2 and CYP2E1 was produced by cross-breeding Cyp1a2-/- mice with Cyp2e1-/- mice. Animals deficient in the expression of both P450s developed normally and exhibited no obvious phenotypic abnormalities. Comparison of the dose-response to APAP (200-1200 mg/kg) indicated that double-null animals were highly resistant to APAP-induced toxicity whereas the wild-type animals were sensitive. Administration of 600 to 800 mg/kg of this drug to male wild-type animals resulted in increased plasma concentrations of liver enzymes (alanine aminotransferase, sorbitol dehydrogenase), lipidosis, hepatic necrosis, and renal tubular necrosis. In contrast, when APAP of equivalent or higher dose was administered to the double-null mice, plasma levels of liver enzymes and liver histopathology were normal. However, administration of 1200 mg of APAP/kg to the double-null mice resulted in infrequent liver lipidosis and mild kidney lesions. Consistent with the protection from hepatotoxicity, the expected depletion of hepatic glutathione (GSH) content was significantly retarded and APAP covalent binding to hepatic cytosolic proteins was not detectable in the double-null mice. Likewise, in vitro activation of APAP by liver microsomes from the double-null mice was approximately one tenth of that in microsomes from wild-type mice. Thus, the protection against APAP toxicity afforded by deletion of both CYP2E1 and CYP1A2 likely reflects greatly diminished production of the toxic electrophile, NAPQI.
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PMID:Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. 977 15

Acetaminophen (APAP) is known to cause centrilobular hepatic necrosis under overdose conditions. This is thought to be mediated via the P450-generated reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI). Initially, NAPQI is detoxified by conjugation with glutathione (GSH), but once GSH is depleted, NAPQI reacts more extensively with hepatic proteins leading to hepatocellular damage. The P450 isoforms thought to be responsible for APAP hepatotoxicity in humans are CYP2E1, CYP1A2, and CYP3A4, and thus, we have investigated the effect of murine Cyp1a2 on APAP hepatotoxicity using Cyp1a2 knockout mice (Liang et al., Proc. Natl. Acad. Sci. USA 93, 1671-1676, 1996). Doses of 250 mg/kg were markedly hepatotoxic in these mice, and surprisingly, deaths only occurred in the knock-out and heterozygote mice over a 24-h period after dosing. Furthermore, there were no significant differences among survivors of any genotype in serum ALT concentrations, a well correlated indicator of APAP hepatotoxicity in mice. Finally, no differences were observed in the urinary metabolites excreted ove the 24-h period, including those derived from GSH conjugation of the major reactive metabolite NAPQI. Consistent with the effects on hepatotoxicity and metabolism, 2 h after hepatotoxic doses (500 mg/kg, i.p.) of APAP no significant differences were observed in total whole liver homogenate nonprotein thiol concentrations among the three genotypes even though hepatic thiols were decreased compared to control animals (> 90%). In addition, when the liver cytosol and microsome samples were examined by immunoblotting for the presence of APAP-protein adducts using a specific antiserum, there were no observable differences in either the intensity of staining or in the spectrum of adducts formed between APAP-dosed mice of any genotype. The cumulative data suggest that Cyp1a2 doses not play a significant role in APAP hepatotoxicity in these mice.
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PMID:Role of CYP1A2 in the hepatotoxicity of acetaminophen: investigations using Cyp1a2 null mice. 987 4

CYP2E1 knockout mice (cyp2e1-/-) were used to investigate the involvement of CYP2E1 in the development of carbon tetrachloride (CCl4)-induced hepatotoxicity. Male cyp2e1-/- and wild-type (cyp2e1+/+) mice were given a single i.p. injection of 1 ml/kg (= 1.59 g/kg) CCl4 and 24 h later liver injury was assessed by elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. No significant increases in serum ALT and AST activities were observed in cyp2e1-/- mice when compared to wild-type counterparts after CCl4 exposure. No detectable abnormality in liver histology was found in cyp2e1-/- mice after CCl4 exposure. In contrast, CCl4 treatment resulted in 442- and 125-fold increases in serum ALT and AST activities, respectively, in wild-type mice. Consistent with the results of serum ALT and AST activities, severe hepatic damage was noted in livers of wild-type mice, indicating the importance of CYP2E1 in mediating the hepatic damage following CCl4 exposure in these mice. In addition, a dramatic decrease in CYP2E1-catalyzed p-nitrophenol activity and complete loss of immunoreactive CYP2E1 were observed in wild-type mice after CCl4 treatment, suggesting that CYP2E1 was degraded during the process of CCl4-induced hepatotoxicity. These studies conclusively demonstrate that CYP2E1 is the major factor involved in the CCl4-induced hepatotoxicity in mice.
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PMID:Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression. 987 5

Nutritional status is a primary factor in the effects of xenobiotics and may be an important consideration in development of safety standards and assessment of risk. One important xenobiotic consumed daily by millions of people worldwide is alcohol. Some adverse effects of ethanol, such as alcohol liver disease, have been linked to diet. For example, ethanol-induced hepatotoxicity in animal models requires diets that have a high percentage of the total calories as unsaturated fat. However, little attention has been given to the role of carbohydrates (or carbohydrate to fat ratio) in the effects of this important xenobiotic on liver injury. In the present study, adult male Sprague-Dawley rats (8-10/group) were infused (intragastrically) diets high in unsaturated fat (25 or 45% total calories), sufficient protein (16%) and ethanol (38%) in the presence or absence of adequate carbohydrate (21 or 2.5%) for 42-55 days (d). Animals infused ethanol-containing diets adequate in carbohydrate developed steatosis, but had no other signs of hepatic pathology. However, rats infused with the carbohydrate-deficient diet had a 4-fold increase in serum ALT levels (p < 0.05), an unexpectedly high (34-fold) induction of hepatic microsomal CYP2E1 apoprotein (p < 0.001), and focal necrosis. The strong positive association between low dietary carbohydrate, enhanced CYP2E1 induction and hepatic necrosis suggests that in the presence of low carbohydrate intake, ethanol induction of CYP2E1 is enhanced to levels sufficient to cause necrosis, possibly through reactive oxygen species and other free radicals generated by CYP2E1 metabolism of ethanol and unsaturated fatty acids.
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PMID:Diet and risk of ethanol-induced hepatotoxicity: carbohydrate-fat relationships in rats. 1004 59

In this experiment, we studied the different changes in activities and protein levels of each subform of hepatic cytochrome P450 and glutathione S-transferase (GST), in chemical-induced liver injury in rats. Rats were administered 1,1-dichloroethylene (DCE), allyl alcohol (AA), bromobenzene (BB) and N,N-dimethylformamide (DMF) p.o. once every two days for 7 times, and decapitated 18 hr after the last administration. DCE and AA showed stronger hepatic toxicity than BB and DMF, as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were higher in DCE and AA treated rats than in BB and DMF groups. Anti-cytochrome P450 inhibitable activity of toluene metabolism and/or immunoblot analysis showed that CYP2E1 and CYP2B1/2 were induced by BB and DMF, but not by the other two chemicals; CYP2C11 was greatly decreased by all of the four toxicants; and CYP1A1/2 was slightly reduced by the four treatments. These changes were reflected in testosterone metabolism. Formation of 6 beta- and 7 alpha-hydroxytestosterone from testosterone was enhanced only in DMF-treated rats, whereas that of 2 alpha- and 16 alpha-hydroxytestosterone was reduced by all of the four chemicals. Serum GST activity was increased only in BB and DMF treated rats, but liver cytosolic GST activity was enhanced by all of the four hepatotoxicants, with higher values in BB and DMF groups than in DCE and AA groups. Immunoblot analysis demonstrated that GST Yp was induced by BB and DMF treatments, and Ya and Yc were increased only by BB. GST Yk and Yb1 were not affected by the treatments. The different change patterns of enzymes by a specific toxin and the similar modifying effect on a specific enzyme by different toxins were discussed in relation to the liver damage and to the heterogeneous distribution of enzymes in liver.
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PMID:Different change patterns of the isozymes of cytochrome P450 and glutathione S-transferases in chemically induced liver damage in rat. 1054 60

Dietary habits are often considered as a pathogenic factor for fatty liver. The impact of dietary intake and steatosis on drug metabolism remains poorly investigated. Our aim was to assess the effect of dietary intake on in vivo cytochrome P450 (CYP) activities in eleven patients with abnormal liver function tests potentially due to fatty liver and associated with a high-sugar diet. Liver function tests, liver volume, aminopyrine breath test (ABT) and chlorzoxazone (CZ) pharmacokinetics (area under the curve, AUC) which are known to reflect CYP2E1 activity were evaluated before and after 2 months restriction of dietary sugar intake. Features at inclusion were an increased BMI (30.3 (SD 3.2) kg/m2), high hepatic volume (1.96 (SD 0.48) litres), hyperechogenic liver parenchyma, elevated liver enzyme activities (alanine aminotransferase (EC 2.6.1.2) 58.6 (SD 17.4) IU/1 with alanine aminotransferase: aspartate aminotransferase (EC 2.6.1.1) ratio > 1), together with a normal ABT value (0.68 (SD 0.21)% specific activity of administered dose of [14C]aminopyrine in breath after 1 h) and a high CYP2E1 activity (CZ AUC 20.3 (SD 7.1) micrograms/ml per h). A dietary sugar restriction was prescribed. On the basis of repeated interviews by the same dietitian, unaware of any clinical and biochemical data, six patients remained complaint to the diet and exhibited reductions in BMI (P < 0.001), serum alanine aminotransferase (P = 0.008), liver volume (P = 0.002) and CYP2E1 activity (P = 0.007), a significant increase in ABT (P < 0.001) together with the disappearance of liver hyperechogenicity at ultrasound. In contrast, the five non-compliant patients did not show any significant change in any of these variables. In conclusion, CYP2E1 activity is induced in patients with perturbations of liver function tests potentially due to fatty liver. In these patients, effective dietary sugar restriction is associated with a reduction in liver volume, a reduction in CYP2E1 activity and an increased aminopyrine metabolism rate.
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PMID:Dietary restriction of energy and sugar results in a reduction in human cytochrome P450 2E1 activity. 1065 74


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