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)

A novel assay system was developed in order to quantitate the nucleophilicity of pure chemicals or tissue extracts. This Nucleophilic Index Value (NIV) assay was based on the ability of putative nucleophiles to inhibit the methylation of cysteine by limiting concentrations of the electrophilic source, N-methyl-N-nitrosourea (MNU). Efficacy of model and cellular nucleophiles was quantitated as nmol cysteine protected by the nucleophile from methylation by MNU/h/mM compound. The NIVs of the pure compounds ascorbate, glutathione, 4-(4-nitrobenzyl)-pyridine (NBP) and indole-3-carbinol (I-3-C) were 2400, 1600, 3 and 0, respectively. When mice were treated with I-3-C by gavage at dosages of 0, 25, 50, 75 or 100 mg/kg body wt, the NIV for ethyl acetate extracts of the livers 1 h after treatment were 0, 33, 47, 52 and 92 nmol cysteine preserved/h/g tissue, respectively. The I-3-C enhancement of NIV was not attributable to ascorbate or glutathione, neither of which were present in the ethyl extracts of liver. When mice were treated with 10 mg N-nitrosodimethylamine (NDMA)/kg body wt 1 h after the varying dosages of I-3-C, the 24 h post-NDMA plasma alanine transaminase (ALT) values were decreased by I-3-C pretreatment in a dose-dependent fashion. Plasma ALT values were used in this study as an indicator of hepatotoxicity. The coefficient of determination, r2, computed from the linear least squares correlation coefficient between NIV and ALT values, was 0.80 (0-100 mg I-3-C/kg) and 0.97 (0-75 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nucleophilic index value: implication in the protection by indole-3-carbinol from N-nitrosodimethylamine cyto and genotoxicity in mouse liver. 337 33

Acetaminophen can be enzymatically bioactivated, which may play a role in cataractogenesis. This study evaluated the relation of dose, sex, plasma drug concentration, cytochromes P-450 (P-450 and P-448) induction, and hepatocellular toxicity to cataractogenic susceptibility in inbred mice and rabbits. C57BL/6 or DBA/2 mice, which respectively are genetically responsive and nonresponsive to P-448 induction, were treated with acetaminophen, 300 to 1000 mg/kg intraperitoneally (ip), following pretreatment with the P-448 inducer 3-methylcholanthrene (3-MC). Bilateral cataracts developed, independent of sex, in 83% of C57BL/6 mice within 4 hr of acetaminophen administration, compared with 7% of DBA/2 mice. A dose-response relation for cataractogenesis was evident in C57BL/6 mice using doses of 300 and 400 mg/kg, with the higher dose producing similar plasma acetaminophen concentrations but twofold higher glucuronide concentrations. Both strains had increased plasma concentrations of glutamic-pyruvic transaminase (GPT). New Zealand white or Chinchilla pigmented rabbits were treated with single or multiple doses of acetaminophen, 500 to 1500 mg/kg/day ip, following pretreatment with a cytochromes P-450 inducer: phenobarbital, 3-MC, or beta-naphthoflavone. Acetaminophen given chronically caused lenticular opacities within 1 week in 19 of 20 rabbits pretreated with P-450 inducers, regardless of pigmentation, but not in animals without prior P-450 induction. No opacities were observed after a single dose of acetaminophen, even with P-450 induction. There was no increase in plasma GPT in rabbits with any treatment. Over 85% of acetaminophen was recovered in urine as a glucuronide conjugate, and the rest as acetaminophen or conjugates with sulfate, cysteine, or N-acetylcysteine. Susceptibility to acetaminophen cataractogenesis can be genetically predetermined and may involve enzymatic bioactivation. possibly independent of hepatic biotransformation and toxicity.
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PMID:Pharmacological studies on the in vivo cataractogenicity of acetaminophen in mice and rabbits. 339 87

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

Pretreatment with buthionine sulfoximine (BSO; 900 mg/kg) induced the elevation of serum GOT and GPT activities in a non-toxic dose of butylated hydroxytoluene (BHT; 250-500 mg/kg) in rats. The elevation of serum enzyme activities was accompanied by a remarked depletion of the hepatic glutathione (GSH) concentration. In contrast, pretreatment with cysteine (100-200 mg/kg) inhibited the elevation of serum enzyme activities at a toxic dose of BHT (1000 mg/kg). The effects of BSO and cysteine on BHT-induced hepatotoxicity in rats are discussed.
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PMID:Effects of buthionine sulfoximine and cysteine on the hepatotoxicity of butylated hydroxytoluene in rats. 361 99

The revelation that many covalent binding estimates are falsely low due to flawed normalization discloses that protection by N-acetyl-L-cysteine against acetaminophen hepatotoxicity is accompanied routinely by a 50 to 80% decline in arylation. Elevated glutathione may be responsible for inhibiting covalent binding but above-normal concentrations have never been demonstrated in vivo after N-acetyl-L-cysteine treatment or separated adequately from other possible hepatoprotective actions including direct reduction of the toxic acetaminophen metabolite by the antidote. This led us to compare the conventional L-isomer of the antidote to its nonphysiologic stereoisomer, N-acetyl-D-cysteine, because the latter should be capable of reducing the toxic metabolite but not of stimulating glutathione biosynthesis. Oral coadministration of N-acetyl-D-cysteine (1200 mg/kg), however, failed in preventing the elevation of serum alanine aminotransferase activity, in decreasing hepatocellular necrosis, in interdicting covalent binding of the toxic metabolite to hepatocellular proteins and in preventing the depletion of liver glutathione caused by 500 mg/kg of acetaminophen. N-acetyl-L-cysteine succeeded in decreasing these measures of acetaminophen hepatotoxicity while driving liver glutathione concentrations 2-3 fold above control values. The L-isomer also increased urinary excretion of glutathione-derived acetaminophen metabolites whereas the D-isomer increased only acetaminophen sulfate excretion and reversed the customary predominance of acetaminophen cysteine over the mercapturic acid conjugate. Liver uptake of N-acetyl-D-cysteine was reflected in organ concentrations 7-fold higher than noted for the L-isomer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice. 372 5

We have reported previously that methoxsalen is a suicide substrate for cytochrome P-450. We now report its effects on the metabolism and toxicity of acetaminophen in mice. Intragastric administration of methoxsalen (125 mumol X kg-1), 30 min before that of acetaminophen (600 mg X kg-1 i.p.), decreased the formation of the mercapturate and cysteine conjugates of acetaminophen, the depletion of glutathione and the in vivo covalent binding of an acetaminophen metabolite to hepatic proteins and prevented the increase in serum glutamic-pyruvic transaminase activity, the appearance of liver lesions and mortality. Methoxsalen (250 mumol X kg-1) also afforded complete protection when given intragastrically 2 hr after acetaminophen (600 mg X kg-1 i.p.). At that time, methoxsalen still decreased in vivo covalent binding measured per whole liver, and permitted a faster recovery of hepatic glutathione. Methoxsalen (180 mumol X kg-1) and N-acetylcysteine (919 mumol X kg-1) exerted additive protective effects when given concomitantly 2 hr after acetaminophen. We conclude that administration of methoxsalen decreases the metabolic activation and the hepatotoxicity of acetaminophen in mice.
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PMID:Pre- or post-treatment with methoxsalen prevents the hepatotoxicity of acetaminophen in mice. 377 10

Weanling, male Sprague-Dawley rats given 10% ethanol in the drinking water and food ad lib. for up to 8 weeks consumed 17% of their calories as ethanol. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver histology by light microscopy were unaffected by this treatment. Similarly, hepatic microsomal NADPH-cytochrome c reductase, ethylmorphine N-demethylase and benzphetamine N-demethylase activities were also not affected by ethanol consumption. On the other hand, cytochrome P-450 content, aniline hydroxylase activity and acetaminophen metabolism as measured by both the cysteine conjugate and the [3H]acetaminophen covalently-bound to microsomal protein were increased significantly by ethanol consumption. The maximal effect was seen by 6 weeks. The 2- to 3-fold increase in aniline and acetaminophen metabolism, the absence of liver damage, and the similarity in weight gains and caloric intakes for controls and treated animals suggest that the rat on 10% ethanol in the drinking water is a reasonable model for studies of the effect of moderate alcohol consumption on specific biochemical pathways.
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PMID:Studies on the effect of chronic consumption of moderate amounts of ethanol on male rat hepatic microsomal drug-metabolizing activity. 393 44

1,2-Dichloroethane produces kidney damage, but the mechanism is unclear. Cysteine conjugates, which could arise from S-(2-chloroethyl)glutathione or S-(2-chloroethyl)cysteine have been identified. In this study, rats given S-(2-chloroethyl)-DL-cysteine (100 mg/kg i.p.) showed significant increases in blood urea nitrogen and urine glucose concentrations. Histopathological examination of kidneys, 36 hr after treatment showed acute proximal tubular nephrosis and punctuate glomerular necrosis. No hepatic lesions were seen and serum glutamate-pyruvate transaminase activities were only elevated slightly. The extent of S-(2-chloroethyl)-DL-cysteine renal toxicity was dose- and time-dependent. Equimolar doses of analogs of S-(2-chloroethyl)-DL-cysteine, S-ethyl-L-cysteine, S-(2-hydroxyethyl)-N-acetyl-DL-cysteine, S-(2-hydroxyethyl)-DL-cysteine, or S-(3-chloropropyl)-DL-cysteine, failed to produce nephrotoxicity; rats given L-cysteine (100 mg/kg i.p.), S-ethyl-L-cysteine (100 mg/kg i.p.) or probenecid (60 mg/kg i.p.) 30 min before receiving S-(2-chloroethyl)-DL-cysteine had significant reductions of the S-(2-chloroethyl)-DL-cysteine-induced blood urea nitrogen and urine glucose elevations. These results show that S-(2-chloroethyl)-DL-cysteine is a potent, selective nephrotoxin that may be responsible for the renal damage associated with 1,2-dichloroethane. The formation of an episulfonium ion plays an important role in S-(2-chloroethyl)-DL-cysteine-induced nephrotoxicity. The protection against renal damage provided by S-ethyl-L-cysteine or probenecid may involve competition with S-(2-chloroethyl)-DL-cysteine for cellular or transport binding sites.
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PMID:Structure-nephrotoxicity relationships of S-(2-chloroethyl)-DL-cysteine and analogs: role for an episulfonium ion. 399 33

The glutathione and cysteine conjugates of the nephrotoxin chlorotrifluoroethene, S-(2-chloro-1,1,2-trifluoroethyl)glutathione (CTFG) and S-(2-chloro-1,1,2-trifluoroethyl)cysteine (CTFC), are potent nephrotoxins in male rats. Morphological changes in the kidneys were observed 1.5 hr after giving 100 mumol/kg of CTFG (i.v.), and severe damage to the proximal tubules was evident 24 hr after treatment; this dose of CTFG caused a 100-fold increase in urine glucose excretion, a 10-fold increase in urine protein excretion and a 4-fold increase in blood urea nitrogen concentrations 24 hr after administration. Administration of 50 mumol/kg of CTFG or 100 mumol/kg of CTFC produced similar lesions and increases in urine glucose excretion rates and blood urea nitrogen concentrations. Administration of 10 mumol/kg of CTFG produced no discernable effect on the kidneys. CTFG and CTFC did not alter plasma glucose concentrations or plasma glutamate-pyruvate transaminase activities. CTFG and CTFC produced time- and dose-dependent loses of cell viability in isolated rat renal tubular cells. The toxicity of CTFG to isolated renal tubular cells was prevented by the gamma-glutamyltransferase inhibitor AT-125, and the toxicity of CTFC and CTFG to isolated cells was prevented by aminooxyacetic acid, an inhibitor of pyridoxal phosphate-dependent enzymes. Moreover, S-(2-chloro-1,1,2-trifluoroethyl)-DL-alpha-methylcysteine, which cannot be metabolized by pyridoxal phosphate-dependent enzymes, was not toxic to isolated renal tubular cells. The data presented support the hypothesis that the nephrotoxicity of chlorotrifluoroethene is due to the enzymatic formation of a glutathione conjugate, which is metabolized to the ultimate nephrotoxin by the sequential action of renal gamma-glutamyltransferase, cysteinylglycine dipeptidase and cysteine conjugate beta-lyase.
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PMID:Nephrotoxicity of S-(2-chloro-1,1,2-trifluoroethyl)glutathione and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, the glutathione and cysteine conjugates of chlorotrifluoroethene. 407 35

Previous metabolic studies of captopril suggest that the rapid dissociation of captopril-plasma protein conjugates in vivo is dependent upon endogenous thiols such as glutathione and cysteine. Consistent with this hypothesis, we have found that cysteine (0.06-3 mM) and glutathione (0.02-1 mM) cleave 14C-captopril-plasma protein conjugates in vitro. Dissociation of the drug-protein conjugate was accompanied by formation of the corresponding mixed disulphide which indicates that the reaction proceeds via a spontaneous thiol-disulphide interchange. Administration of high doses (50-300 mg/kg) of CP produced a time-dependent and dose-dependent decrease in hepatic glutathione concentrations in the mouse and the rat. The depletion of glutathione observed was similar to that produced by equimolar doses of D-penicillamine and paracetamol. Acute and chronic (7 days) administration of captopril (100 mg/kg) produces the same (11-12%) depletion of hepatic glutathione. However, changes in liver function as determined by elevation of serum glutamic-pyruvic transaminase was only observed at doses of 200 and 300 mg/kg. Thus, although thiol-disulphide interactions between captopril and plasma proteins may contribute to the perturbation of hepatic glutathione concentrations, it is unlikely that this process will be of toxicological significance during therapeutic administration of captopril.
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PMID:Drug protein conjugates--VI. Role of glutathione in the metabolism of captopril and captopril plasma protein conjugates. 636 Jan 77


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