Search results for "Adduct"
showing 10 items of 320 documents
Multi-step metabolic activation of benzene. Effect of superoxide dismutase on covalent binding to microsomal macromolecules, and identification of gl…
1980
Abstract Incubation of [ 14 C]benzene or [ 14 C]phenol with liver microsomes from untreated rats, in the presence of a NADPH-generating system, gave rise to irreversible binding of metabolites to microsomal macromolecules. For both substrates this binding was inhibited by more than 50% by addition of superoxide dismutase to the incubation mixtures. The decrease in binding was compensated for by accumulation of [ 14 C]hydroquinone, indicating superoxide-mediated oxidation of hydroquinone as one step in the activation of benzene to metabolites binding to microsomal macromolecules. Since our previous work had shown that binding occurred mainly with protein rather than ribonucleic acid and was …
Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats
2013
Hydroxytyrosol (HT), one of the major polyphenols present in olive oil, is known to possess a high antioxidant capacity. The aim of the present study was to investigate dose dependent (0, 1, 10 and 100 mg/kg) alterations in the metabolism of HT in rats since it has been reported that metabolites may contribute to biological effects. Special attention was paid to the activation of the semiquinone quinone oxidative cycle and the formation of adducts with potential deleterious effects. Thus, we developed a novel analytical methodology to monitor the in vivo formation of the HT mercapturate, N-acetyl-5-S-cysteinyl-hydroxytyrosol in urine samples. Biomarkers of hepatic and renal toxicity were ev…
Nitrosoureas Modes of Action and Perspectives in the Use of Hormone Receptor Affine Carrier Molecules
1989
Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds are discussed. CNUs are alkylating agents that form DNA-DNA cross-links as well as 2-chloroethylated and 2-hydroxyethylated adducts, the N-7-position of guanine being the predominantly alkylated site. A close correlation exists between the potential of a given compound to induce DNA-DNA cross-links and its antineoplastic effectiveness. However, levels of DNA-DNA cross-linking in bone marrow and extent of myelosuppression as measured in rodents are also closely correlated. The design of new cross-linking analogues capable of directing the antineoplastically re…
Sulfotransferase-mediated chlorination of 1-hydroxymethylpyrene to a mutagen capable of penetrating indicator cells.
1990
Methylated polycyclic aromatic hydrocarbons are common in the human environment. Many of them are stronger carcinogens than their purely aromatic congeners. They may be metabolized to benzylic alcohols. We report here on biochemical and toxicological characteristics of 1-hydroxymethylpyrene (HMP), a typical representative of this class of compounds. Rat liver cytosol, fortified with 3'-phosphoadenosine-5'-phosphosulfate, converted HMP into its sulfate ester (HMPS), HMPS bound covalently to isolated DNA. In physiological buffer at 37 degrees C, HMPS had a half-life of 2 min, the major decomposition product being HMP. Thus, cyclic activation is possible. When Cl- anions were present at physio…
Kinetics of tienilic acid bioactivation and functional generation of drug–protein adducts in intact rat hepatocytes
2005
13 pages; Drug-induced autoimmune hepatitis is among the most severe hepatic idiosyncratic adverse drug reactions. Considered multifactorial, the disease combines immunological and metabolic aspects, the latter being to date much better known. As for many other model drugs, studies on tienilic acid (TA)-induced hepatitis have evidenced the existence of bioactivation during the hepatic oxidation of the drug, allowing the identification of the neoantigen of anti-LKM2 autoantibodies and the pathway responsible for its formation. However, most of these results are based on the use of microsomal fractions whose relevance to the liver in vivo still needs to be established. In the more complex int…
Carcinogenic Etheno DNA Adducts in Alcoholic Liver Disease: Correlation with Cytochrome P-4502E1 and Fibrosis.
2017
BACKGROUND One mechanism by which alcoholic liver disease (ALD) progresses is oxidative stress and the generation of reactive oxygen species, among others due to the induction of cytochrome P-4502E1 (CYP2E1). Experimental data underline the key role of CYP2E1 because ALD could be partially prevented in rats by the administration of the specific CYP2E1 inhibitor chlormethiazole. As CYP2E1 is linked to the formation of carcinogenic etheno DNA adducts in ALD patients, a causal role of alcohol-induced CYP2E1 in hepatocarcinogenesis is implicated. The purpose of this study was to investigate CYP2E1 induction in ALD, and its correlation with oxidative DNA lesions and with hepatic histology. METHO…
Selective targeting of PARP-1 zinc finger recognition domains with Au(III) organometallics
2018
The binding of Au(iii) complexes to the zinc finger domain of the anticancer drug target PARP-1 was studied using a hyphenated mass spectrometry approach combined with quantum mechanics/molecular mechanics (QM/MM) studies. Competition experiments were carried out, whereby each Au complex was exposed to two types of zinc fingers. Notably, the cyclometallated Au-C^N complex was identified as the most selective candidate to disrupt the PARP-1 zinc finger domain, forming distinct adducts compared to the coordination compound Auphen.
Hexakis-adducts of [60]fullerene as molecular scaffolds of polynuclear spin-crossover molecules
2021
A family of hexakis-substituted [60]fullerene adducts endowed with the well-known tridentate 2,6-bis(pyrazol-1-yl)pyridine (bpp) ligand for spin-crossover (SCO) systems has been designed and synthesized. It has been experimentally and theoretically demonstrated that these molecular scaffolds are able to form polynuclear SCO complexes in solution. UV-vis and fluorescence spectroscopy studies have allowed monitoring of the formation of up to six Fe(ii)–bpp SCO complexes. In addition, DFT calculations have been performed to model the different complexation environments and simulate their electronic properties. The complexes retain SCO properties in the solid state exhibiting both thermal- and …
Adducts of free-base meso-tetraarylporphyrins with trihaloacetic acids: Structure and photostability
2020
Abstract Four diverse meso-tetraarylporphyrins in the form of diprotonated adducts with trifluoro-, trichloro-, tribromoacetic acids and acetic acid were investigated in benzene solution. Despite similar structural distortion of the chromophore system due to protonation, the respective adducts demonstrated different photostability when exposed to UV irradiation. The trifluoro- and trichloroacetic adducts, and the acetic acid one, showed some common features both molecular and in the mechanism of photodegradation. However, the tribromo-derivative decayed according to a different kinetic scheme, revealing a considerable impact of the bromine atoms upon the pyrrole units of the porphyrin macro…
Identification and quantification of metabolite conjugates of activated cyclophosphamide and ifosfamide with mesna in urine by ion-pair extraction an…
1985
The high bladder toxicity of the alkylating oxazaphosphorine anticancer drugs, cyclophosphamide and ifosfamide is effectively reduced by the concomitant administration of mesna (sodium 2-mercaptoethane sulphonate). The formation and rapid urinary excretion of conjugates of the activated (4-hydroxylated) oxazaphosphorine metabolites with mesna has been suggested as the pharmacological basis for the selective detoxification, but separation and identification of such metabolites in vivo have been extremely difficult due to their high polarity and chemical lability. In this study an ion-pair extraction procedure in combination with positive and negative ion fast atom bombardment mass spectromet…