Metabolic activation of carcinogens.

The material presented in this review deals with the hypothesis that the nephrotoxicity of certain halogenated alkanes and alkenes is associated with hepatic biosynthesis of glutathione S-conjugates, which are further metabolized to the corresponding cysteine S-conjugates. Some glutathione or cysteine S-conjugates may be direct-acting nephrotoxins, but most cysteine S-conjugates require bioactivation by renal, pyridoxal phosphate-dependent enzymes, such as cysteine conjugate beta-lyase (beta-lyase). The biosynthesis of glutathione S-conjugates is catalyzed by both the cytosolic and the microsomal glutathione S-transferases, although the latter enzyme is a better catalyst for the reaction of haloalkenes with glutathione. When glutathione S-conjugate formation yields sulfur mustards, as occurs with vicinal-dihaloethanes, the S-conjugates are direct-acting toxins. In contrast, the S-conjugates formed from fluoro- and chloroalkenes yield S-alkyl- or S-vinyl glutathione conjugates, respectively, which are metabolized to the corresponding cysteine S-conjugates by gamma-glutamyltransferase and dipeptidases; inhibition of these enzymes blocks the toxicity of the glutathione S-conjugates. The cysteine S-conjugates must be metabolized by beta-lyase for the expression of toxicity; the beta-lyase inhibitor aminooxyacetic acid blocks the toxicity of cysteine S-conjugates, and the corresponding alpha-methyl cysteine S-conjugates, which cannot be metabolized by beta-lyase, are not toxic. Moreover, probenecid, an inhibitor of renal anion transport system, blocks the toxicity of cysteine S-conjugates, which cannot be metabolized by beta-lyase, are not toxic. Moreover, probenecid, an inhibitor of renal anion transport system, blocks the toxicity of cysteine S-conjugates. Homocysteine S-conjugates are also potent cyto- and nephrotoxins. The high renal content of gamma-glutamyltransferase and the renal anion transport system are probably determinants of kidney tissue as a target site. Biochemical studies indicate that renal mitochondrial dysfunction is produced by the cysteine S-conjugates. Finally, some of the glutathione and cysteine conjugates are mutagenic in the Ames test, and reactive intermediates formed by the action of beta-lyase may contribute to the nephrocarcinogenicity of certain chloroalkenes.

Biosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites.

The possibilities and limitations of using mercapturic acids and protein and DNA adducts for the assessment of internal and effective doses of electrophilic chemicals are reviewed. Electrophilic chemicals may be considered as potential mutagens and/or carcinogens. Mercapturic acids and protein and DNA adducts are considered as selective biomarkers because they reflect the chemical structure of the parent compounds or the reactive electrophilic metabolites formed during biotransformation. In general, mercapturic acids are used for the assessment of recent exposure, whereas protein and DNA adducts are used for the assessment of semichronic or chronic exposure. 2-Hydroxyethyl mercapturic acid has been shown to be the urinary excretion product of five different reactive electrophilic intermediates. Classification of these electrophiles according to their acid-base properties might provide a tool to predict their preference to conjugate with either glutathione and proteins or with DNA. Constant relationships appear to exist in the cases of 1,2-dibromoethane and ethylene oxide between urinary mercapturic acid excretion and DNA and protein adduct concentrations. This suggests that mercapturic acids in some cases may also play a role as a biomarker of effective dose. It is concluded that simultaneous determination of mercapturic acids, protein and DNA adducts, and other metabolites can greatly increase our knowledge of the specific roles these biomarkers play in internal and effective dose assessment. If the relationship between exposure and effect is known, similar to protein and DNA adducts, mercapturic acids might also be helpful in (individual) health risk assessment.

Mercapturic acids, protein adducts, and DNA adducts as biomarkers of electrophilic chemicals

The psychostimulants methylphenidate, amphetamine and pemoline are among the most common medications used today in child and adolescent psychiatry for the treatment of patients with attention-deficit hyperactivity disorder. Frequently, these medications are used in combination with other medications on a short or long term basis. The present review examines psychostimulant pharmacology, summarises reported drug-drug interactions and explores underlying pharmacokinetic and pharmacodynamic considerations for interactions. A computerised search was undertaken using Medline (1966 to 2000) and Current Contents to provide the literature base for reports of drug-drug interactions involving psycho-stimulants. These leads were further cross-referenced for completeness of the survey. Methylphenidate appears to be more often implicated in pharmacokinetic interactions suggestive of possible metabolic inhibition, although the mechanisms still remain unclear. Amphetamine was more often involved in apparent pharmaco-dynamic interactions and could potentially be influenced by medications affecting cytochrome P450 (CYP) 2D6. No published reports of drug interactions involving pemoline were found. The α2-adrenergic agonists clonidine and guanfacine have been implicated in several interactions. Perhaps best documented is their antagonism by tricyclic antidepressants and phenothiazines. In additional, concurrent β-blocker use, or abrupt discontinuation, can lead to hypertensive response. Although there are few published well-controlled interaction studies with psycho-stimulants and α2-adrenergic agonists, it appears that these agents may be safely coadministered. The interactions of monoamine oxidase inhibitors with psycho-stimulants represent one of the few strict contraindications.

Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder.

Bioactivation of xenobiotics by formation of toxic glutathione conjugates.

The metabolic formation of N-acetyl-S-2-hydroxyethyl-L-cysteine from tetradeutero-1,2-dibromoethane. relative importance of oxidation and glutathione conjugation in vivo.

1. In urine of rats given vinylbital (5-vinyl-5-(1'-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1'-methylbutyl)barbituric acid, were identified. Rats synthetic 1',2'-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1',2'-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide. 2. Attempts to synthesize 1',2'-dihydroxyvinylbital from 1',2'-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1'-methylbutyl)barbituric acid by a 'retro-aldol type' reaction. 3. In rat liver microsomal preparation 1',2'-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8 mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1'-methylbutyl)barbituric acid as end-product of this enzyme reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital. 4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6 +/- 1.7% of the dose (n = 5), respectively. Upon administration of 1',2-epoxyvinylbital, 59.8 +/- 14.2% of the dose (n = 5) was excreted as 5-(1'-methylbutyl)barbituric acid. 5. In 60 h urine of three human volunteers who had taken 150 mg of vinylbital orally, 2.6 +/- 1.7% of the dose was excreted as vinylbitaland 11.0 +/- 4.1% as 5-(1'-methylbutyl) barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.

The epoxide-diol pathway in the metabolism of hexobarbital in rat and man

Epoxide-diol pathway in the metabolism of hexobarbital in rat and man

1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half-live of 11.0 +/- 1.2 h (n=4). Peak levels were reached at 2.7 +/- 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/- 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/- 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half-lives were slightly shorter than the corresponding plasma half-lives.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1979.tb01026.x

Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration.

Simultaneous determination of blood concentrations of methohexital and its hydroxy metabolite by gas chromatography and identification of 4'-hydroxymethohexital by combined gas--liquid chromatography--mass spectrometry

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

D.D. Breimer

Author Tools

Chat about Author