Evidence for the Bioactivation of 4-Nonylphenol to Quinone Methide and ortho-Benzoquinone Metabolites in Human Liver Microsomes.

06:16 EST 4th March 2015 | BioPortfolio

Summary of "Evidence for the Bioactivation of 4-Nonylphenol to Quinone Methide and ortho-Benzoquinone Metabolites in Human Liver Microsomes."

4-Nonylphenol (4-NP) is a well-known toxic environmental contaminant. The major objective of the present study was to identify reactive metabolites of 4-NP. Following incubations of 4-NP with NADPH- and GSH-supplemented human liver microsomes, 6 GSH conjugates, along with 19 oxidized metabolites, were detected by UPLC/Q-TOF mass spectrometry utilizing the mass defect filter method. Several authentic key metabolite standards were chemically synthesized for structural identification. Three GSH conjugates were found to derive from quinone methide intermediates, and the other three resulted from ortho-benzoquinone intermediates. Conjugation of the quinone methides with GSH produced benzylic-orientated GSH conjugates by 1,6-addition, while the reaction of the ortho-benzoquinone intermediates offered aromatic-orientated GSH conjugates. The conversion of 4-NP to the quinone methides and ortho-hydroquinones required cytochromes P450, specifically CYPs1A2, 2C19, 2D6, 2E1, and 3A4, while the oxidation of ortho-benzohydroquinones to the corresponding benzoquinones was apparently independent of microsomal enzymes. The ortho-benzoquinone derived from 4-NP was isomerized to the corresponding hydroxyquinone methide, and the former dominated the latter at a rate of approximately 20:1. The findings of the quinone methide and benzoquinone metabolites intensified the concern on the impact of 4-NP exposure on human health.


Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology, Department of Pediatrics, University of Washington, Seattle

Journal Details

This article was published in the following journal.

Name: Chemical research in toxicology
ISSN: 1520-5010


PubMed Articles [8637 Associated PubMed Articles listed on BioPortfolio]

Quinone-Methide Species, A Gateway to Functional Molecular Systems: From Self-Immolative Dendrimers to Long-Wavelength Fluorescent Dyes.

Conspectus Over the last 30 years, the quinone-methide elimination has served as a valuable tool for achieving various important molecular functions. Molecular adaptors based on quinone-methide or aza...

Oxidative Quenching of Quinone Methide Adducts Reveals Transient Products of Reversible Alkylation in Duplex DNA.

ortho-Quinone methides (ortho-QM) and para-quinone methides are generated by xenobiotic metabolism of numerous compounds including environmental toxins and therapeutic agents. These intermediates are ...

Antioxidant activity and mechanism of the abietane-type diterpene ferruginol.

The antioxidant activity of the abietane-type diterpene ferruginol was evaluated by comparison with that of carnosic acid, ( ± )-α-tocopherol and dibutylhydroxytoluene using 2,2-diphenyl-1-picrylh...

Dicoumarol inhibits rat NAD(P)H:quinone oxidoreductase in vitro and induces its expression in vivo.

Dicoumarol is known to act as an inhibitor of NAD(P)H:quinone oxidoreductase (NQO1). This cytosolic reductase significantly contributes to the genotoxicity of the nephrotoxic and carcinogenic alkaloid...

Characterization of human Cytochrome P450s involved in the bioactivation of tri-ortho-cresyl phosphate.

Tri-ortho-cresyl phosphate (ToCP) is a multi-purpose organophosphorus compound that is neurotoxic and suspected to be involved in the aerotoxic syndrome in humans. It has been reported that not ToCP i...

Clinical Trials [896 Associated Clinical Trials listed on BioPortfolio]

To Compare SH T00658ID Over Ortho Tri-Cyclen Lo (US/Canada)

The objective of the study is to compare the oral contraceptive (OC) SH T00658ID over Ortho Tri-Cyclen Lo administered for 13 cycles to healthy female volunteers between 18 and 50 years of...

Study to Assess the Effect of BMS-790052 on the Pharmacokinetics of Ortho Tri-Cyclen® in Healthy Female Subjects

The purpose of this study is to assess the effect of BMS-790052 on the pharmacokinetics of Ortho Tri-Cyclen® in healthy female subjects.

Atazanavir and Ritonavir (ATV/RTV) and an Oral Contraceptive in Healthy Females

The purpose of this study is to administer a combined oral contraceptive (ethinyl estradiol and norgestimate) with the HIV treatment of atazanavir and ritonavir to healthy females in order...

Drug-Drug Interaction Study Between Colchicine and Atorvastatin

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4/5 competitive and...

Plasma Pharmacokinetics of Alkylresorcinol Metabolites; New Candidate Biomarkers for Whole Grain Rye and Wheat Intake

The purpose of this study is to investigate the kinetics of two known alkylresorcinol metabolites in human subjects after intake of high-fiber rye bread. Whole grain rye is the most abunda...

Medical and Biotech [MESH] Definitions

A plant genus of the family TAXODIACEAE. Members contain taxodione and taxodone, which are diterpenoid quinone methide tumor inhibitors.

NAD(P)H:(quinone acceptor) oxidoreductases. A family that includes three enzymes which are distinguished by their sensitivity to various inhibitors. EC (NAD(P)H DEHYDROGENASE (QUINONE);) is a flavoprotein which reduces various quinones in the presence of NADH or NADPH and is inhibited by dicoumarol. EC (NADH dehydrogenase (quinone)) requires NADH, is inhibited by AMP and 2,4-dinitrophenol but not by dicoumarol or folic acid derivatives. EC (NADPH dehydrogenase (quinone)) requires NADPH and is inhibited by dicoumarol and folic acid derivatives but not by 2,4-dinitrophenol.

One ring heterocyclic compounds defined by C6H7NO. Permitted are any degree of hydrogenation, any substituents and any ortho-fused or ortho-peri-fused ring systems.

A preconceived judgment made without adequate evidence and not easily alterable by presentation of contrary evidence.

A lipid-soluble benzoquinone which is involved in ELECTRON TRANSPORT in mitochondrial preparations. The compound occurs in the majority of aerobic organisms, from bacteria to higher plants and animals.

Search BioPortfolio:

Relevant Topic

Latest News Clinical Trials Research Drugs Reports Corporate
Pediatrics is the general medicine of childhood. Because of the developmental processes (psychological and physical) of childhood, the involvement of parents, and the social management of conditions at home and at school, pediatrics is a specialty. With ...


Searches Linking to this Article