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 has been shown to be cataractogenic in mice and rabbits. C57BL/6 and DBA/2 mice respectively are genetically susceptible and resistant to the induction of cytochrome P-448 by 3-methylcholanthrene (3-MC). This isoenzyme is thought to bioactivate acetaminophen to a toxic reactive intermediate. These two murine strains also are correspondingly susceptible and resistant to acetaminophen cataractogenesis. To evaluate the potential role of enzymatic bioactivation as a determinant of acetaminophen cataractogenesis, C57BL/6 and DBA/2 mice were treated with acetaminophen, 300 or 400 mg/kg intraperitoneally (ip), with or without pretreatment 48 hr earlier using 3-MC, 200 mg/kg ip. Lenticular cataracts were evaluated using the unaided eye and a slit lamp, and hepatotoxicity was evaluated by determination of peak plasma concentration of alanine aminotransferase (ALT). Plasma concentrations of acetaminophen and metabolites, particularly the glutathione (GSH)-derived conjugates (cysteine and mercapturic acid) reflecting enzymatic bioactivation, were measured by high-performance liquid chromatography. Cataracts developed only in C57BL/6 mice pretreated with 3-MC, occurring in 1 of 5 and 5 of 5 animals treated respectively with 300 and 400 mg/kg of acetaminophen. Comparing these two groups of induced C57BL/6 mice, production of the cysteine conjugate of acetaminophen was 2.5-fold higher with the 400 mg/kg dose of acetaminophen (p less than 0.05). Compared to their respective dose-matched, noninduced controls, cysteine conjugate production in the 300 and 400 mg/kg dose groups of induced C57BL/6 mice respectively was 3-fold and 4-fold higher (p less than 0.05). No DBA/2 mice developed cataracts. No mercapturic acid conjugate was detectable in the plasma of DBA/2 mice, and production of the cysteine conjugate was not altered in this strain by increasing the dose of acetaminophen or by pretreatment with 3-MC. The mean peak plasma concentration of the cysteine conjugate, reflecting acetaminophen bioactivation, was 5-fold higher in animals developing cataracts compared with those without cataracts (p less than 0.001). Plasma concentrations of unmetabolized acetaminophen were similar in all groups and unrelated to the development of cataracts. All mice of both strains pretreated with 3-MC showed evidence of hepatotoxicity, indicating a dissociation between hepatotoxic and cataractogenic susceptibility.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Metabolic evidence for the involvement of enzymatic bioactivation in the cataractogenicity of acetaminophen in genetically susceptible (C57BL/6) and resistant (DBA/2) murine strains. 340 97

Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.
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PMID:Mechanistic studies of the inhibition of hepatic uroporphyrinogen decarboxylase in C57BL/10 mice by iron-hexachlorobenzene synergism. 380 Sep 66

The hepatotoxic effect of carbon tetrachloride (CCl4), reflected by augmented blood aspartate aminotransferase and alanine aminotransferase activities and the extent of histological liver damage, was observed following oral administration of CCl4 to rats. A marked increase of blood transaminase activities and severe degeneration of hepatocytes in the centrilobular region were detected 1-2 days after the administration, while the cytochrome P-450 content and the drug metabolizing activity in livers were depressed immediately after the administration. Based on these results, the effect of CCl4 on hepatic cytochrome P-450 and the histological pattern of liver cells was observed using tissue samples obtained from various liver lobes of rats given CCl4 24 hr previously. Dose-dependent inactivation of cytochrome P-450 by the administration of CCl4 was observed throughout the liver, with the most extensive decrease in the cytochrome content in the median lobe. The extent of liver damage (hydropic swelling degeneration and central necrosis in lobule) was also greater in the median and right liver lobes than in the left lobe. When a small amount of CCl4 was administered, degeneration of liver cells was detected only in the median and right lobes with only slight degeneration in the left lobe. These results indicate different susceptibilities of rat liver lobes to CCl4.
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PMID:Carbon tetrachloride-induced hepatotoxicity in rats: evidence for different susceptibilities of rat liver lobes. 688 48

The effects of anabolic-androgenic steroid administration and exercise training on various aspects of hepatic function were investigated in sedentary and trained (treadmill for 12 wk) male and female rats treated orally with fluoxymesterone or methylandrostanolone (2 mg.kg-1 body weight, 5 d.wk-1 for 8 wk). The mean values of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, and total- and high-density lipoprotein-cholesterol remained within normal range in all groups of male animals. The same is true for female rats, except for an increase in alkaline phosphatase activity in the steroid-treated groups. Hepatic microsomal aniline p-hydroxylase activity was reduced in male and increased in female rats by either steroid, whereas no significant effect was detected on 7-ethoxycoumarin deethylase activity. The levels of cytochrome P-450 and cytochrome b5 were markedly decreased by the anabolic-androgenic steroid treatment in male rat microsomes, but neither the steroid administration nor exercise training induced significant changes in the cytochrome levels of female rat livers. Taking into account the significant increase in microsomal protein yield elicited by fluoxymesterone or methylandrostanolone treatment both in males and females, it is noteworthy that the total monooxygenase activities and cytochrome P-450 content, expressed on a per gram liver basis, were significantly increased in female whereas they were apparently unchanged in male rats. In conclusion, the present data show that the prolonged ingestion of high doses of anabolic-androgenic steroids, either with or without concurrent exercise training, can modify in a sex-dependent manner the capacity of rat liver to metabolize drugs without affecting classical serum indicators of hepatic function.
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PMID:Effect of training and anabolic-androgenic steroids on drug metabolism in rat liver. 835 Jul 4

The aim of this study was an experimental assessment of the influence of caffeine on the symptoms of the toxic action of paracentamol in mice as well as a detailed analysis if paracetamol pharmacokinetics in men receiving caffeine at the same time. The toxicologic investigations were performed in 620 Swiss mice. The LD50 and LD100 were determined after an administration of paracetamol intraperitoneally. The effects of two doses of caffeine on the survival time and number of animal deaths were investigated. The degree of hepatic damage was assessed on the basis of biochemical serum criteria, i.e. alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and concentration of bilirubin in serum, as well as on the basis of biochemical investigations of liver homogenates, estimating the concentration of reduced glutathione and P-450 cytochrome in the liver. The anatomicopathologic liver evaluation was also performed, including histological and histopathological examinations (glycogen, lipids). The pharmacological investigations were performed in 9 healthy volunteers in two randomized subgroups with the use of a cross-over method twice at one week intervals. The blood paracetamol level was determined according to the method of Thoma et al. The course of changes of paracetamol plasma levels was described with a one-compartment model for extravascular administration of the drug. The biexponential equation, describing the assumed model, was solved with the method of the smaller squares, using non-linear approximation. (Tab 1-6, Fig. 1-3). The experimental studies demonstrated a decrease in both the acute toxicity and hepatotoxic action of paracetamol administered in combination with caffeine, which was indicated by a significant decrease in aminotransferase and alkaline phosphatase activity and in concentration of bilirubin as well as by an increase in the concentration of P-450 cytochrome and GSH in the liver which decreased after administration of paracetamol alone and also by limitation or lack of hepatic necrosis. The pharmacokinetic calculations in men demonstrated an interaction between paracetamol and caffeine which was indicated by a decrease in plasma paracetamol levels, by a smaller surface under the curve of changes of paracetamol levels indicating faster elimination of the drug after simultaneous administration with caffeine. Therefore, paracetamol preparations with caffeine may be less toxic than paracetamol alone.
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PMID:[Influence of caffeine on toxicity and pharmacokinetics of paracetamol]. 861 54

1. 2-(Allylthio)pyrazine protects the liver against acetaminophen- and carbon tetrachloride-induced injury through inhibition of cytochrome P4502E1 and induction of glutathione S-transferases (GSTs). By comparison, the effects of allylthiobenzimidazole (ATB) on the levels of several hepatic cytochrome P450, microsomal epoxide hydrolase (mEH) and GST expression have been studied in the rat herein. 2. Western immunoblotting analyses revealed that ATB treatment (50 mg/kg/day for 5 days) failed to alter cytochrome P4501A2, P4502B1/2 and P4502E1 levels in the liver, whereas the expression of P4502C11 was reduced approximately 50% by ATB. 3. Treatment of rat with a single dose of ATB resulted in 2-21-fold increases in mEH mRNA levels at 24 h with an ED50 = 60 mg/kg. mEH mRNA level was elevated 9- and 21-fold at 12 and 24 h after treatment at 200 mg/kg respectively as compared with control. Western blot analysis revealed that ATB induced mEH protein levels by 2-fold relative to control. 4. ATB induced the major GST mRNA levels as a function of dose, resulting in rGSTA2, rGSTA3/5 and rGSTM1 mRNA levels elevated by 20-, 6- and 8-fold at 24 h respectively. The relative rGSTM2 mRNA level was minimally affected. Time-course studies showed that mEH, rGSTA2 and rGSTM1 mRNA levels were significantly increased at 12 and 24 h after ATB treatment, returning to control levels by 48 h. Treatment of rat with ATB (20-50 mg/kg/day for 5 days) resulted in 2-3-fold increases in mEH, rGSTA1/2, rGSTA3/5 and rGSTM1 mRNA levels with the induction of GST subunits. 5. ATB failed to block carbon tetrachloride-induced liver toxicity in rat and mouse. ATB treatment (50 mg/kg day for 3 days) prior to a lethal dose of acetaminophen significantly reduced acetaminophen-induced liver toxicity in mouse, as assessed by both plasma alanine aminotransferase activity and histopathological examination. The 30-day survival rate of mouse gamma-irradiated at 8 Gy failed to be improved by ATB pretreatment (100 mg/kg/day for 2 days). 6. These results provided evidence that ATB stimulated mEH and GST gene expression at early times and reduced the P4502C11 level in the absence of P4502E1 suppression. ATB was only partially effective in protecting the liver against toxicant-induced injury despite the presence of allylthio moiety in its chemical structure.
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PMID:Partial hepatoprotective effects of allylthiobenzimidazole in the absence of cytochrome P4502E1 suppression: effects on epoxide hydrolase, rGSTA2, rGSTA3/5, rGSTM1 and rGSTM2 expression. 957 20

Cellular regeneration and tissue repair greatly influence the outcome of acute carbon tetrachloride (CCl4) hepatotoxicity. This study examined the temporal kinetics of cellular regeneration and tissue repair processes in male and female Sprague Dawley (SD) rats following an acute CCl4 exposure (0.8 ml/kg, i.p.). In female rats, hepatic damage peaked at 24 h following the treatment and was approximately 2.5-fold (AST 2.7-fold, ALT 2.3 fold) greater than the damage observed in male rats. The hepatic damage in male rats appeared to peak by 3 h post-exposure and did not significantly change through the 36-h time-point. The activity of cytochrome P 4502E1 was 20% greater in male rats and did not correlate with the magnitude of hepatic damage. Morphometric analysis of cell cycle indices revealed that cellular regeneration was significantly greater in female rats as compared to male rats at 48 h and corresponded proportionally to the extent of liver damage. This study demonstrated that female SD rats respond more severely to acute CCl4 hepatotoxicity than male SD rats and the extent of tissue repair and cellular regeneration was greater in female rats. Furthermore, our results suggest that tissue repair is unlikely to result in accounting for the different responses exhibited by male and female SD rats to CCl4 hepatotoxicity.
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PMID:Evaluation of sex difference in tissue repair following acute carbon tetrachloride toxicity in male and female Sprague-Dawley rats. 986 77

In the mouse, retinol administration attenuates carbon tetrachloride (CCl4)-induced hepatic injury. We have investigated the role of cytochrome P4502E1 (CYP2E1) in this interaction. Male Swiss Webster mice were administered retinol (75 mg/kg/d) or vehicle for 3 days prior to CCl4 (30 microl/kg, ip). Hepatotoxicity produced by CCl4 was assessed by plasma alanine aminotransferase (ALT) activity and light microscopy (ALT activity of 1391+/-430 vs. 274+/-92 IU/L for vehicle + CCl4 and retinol + CCl4 treatments respectively, p < 0.05). Retinol's attenuation of liver injury was maintained when CCl4 was administered 48 h after the conclusion of the retinol pretreatment. Aniline hydroxylation activity, an indicator of CYP2E1 catalytic activity, determined on day 4 was 33.8% of untreated control in vehicle + CCl4 treatments while the retinol + CCl4 treatment group was 94.2% of untreated control. Additionally, CYP2E1 immunoreactive protein was 78% lower in vehicle + CCl4 vs. retinol + CCl4 treatment groups. Attenuation of potentiated hepatotoxicity was also observed when CYP2E1 was induced by acetone (ALT activity of 3119+/-1066 vs. 247+/-77 IU/L for vehicle and retinol treatments respectively, p < 0.05). In the mouse, retinol itself does not alter constitutive or inducible CYP2E1 expression. However, in combination with CCl4 retinol does reduce the amount of CCl4 bioactivated to its toxic metabolite. We conclude that retinol attenuates CCl4-induced hepatotoxicity by causing a decrease in CCl4 bioactivation but does not cause a decrease in CYP2E1 expression.
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PMID:Role of cytochrome P4502E1 in retinol's attenuation of carbon tetrachloride-induced hepatotoxicity in the Swiss Webster mouse. 1056 6

Mice were fed with high zinc diet (15 g/kg) for 3 weeks. High zinc could cause liver toxicity: 1. inhibiting the activity of GOT and GPT in liver homogenate, reducing GSH and glycogen contents. 2. increasing the activity of aniline hydroxylase and inhibiting the activities of NADPH-cytochrome C reducease, benzo-phytamine-N-demethylase and glutathione S-transferase. The activities of cytochrome P450 and cytochrome b5 were not obviously changed 3. increasing microsomal membrane fluidity in the superficial layers, but not in the deep layers.
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PMID:[Effects of high dietary zinc on liver function, hepatic drug metabolism enzymes and membrane fluidity in mice]. 1068 26

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.
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PMID:The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. 1077 42


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