Advertisement

Topics

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

06:00 EDT 17th September 2010 | 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.

Affiliation

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
Pages:

Links

DeepDyve research library

PubMed Articles [9784 Associated PubMed Articles listed on BioPortfolio]

Total Synthesis and Structure Revision of (-)-Siphonodictyal B and Its Biomimetic Conversion into (+)-Liphagal.

The structure of siphonodictyal B has been reassigned on the basis of the total synthesis of both possible C-8 epimers. The revised structure of siphonodictyal B was converted into liphagal by acid ca...

In cellulo monitoring of quinone reductase activity and reactive oxygen species production during the redox cycling of 1,2 and 1,4 quinones.

Quinones are highly reactive molecules that readily undergo either one- or two-electron reduction. One-electron reduction of quinones or their derivatives by enzymes such as cytochrome P450 reductase ...

Total Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels-Alder Reaction.

The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels-Alder reaction of (-)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highl...

Formation and stability of gas-phase o-benzoquinone from oxidation of ortho-hydroxyphenyl: a combined neutral and distonic radical study.

Gas-phase product detection studies of o-hydroxyphenyl radical and O2 are reported at 373, 500, and 600 K, at 4 Torr (533.3 Pa), using VUV time-resolved synchrotron photoionisation mass spectrometry. ...

Detecting reactive drug metabolites for reducing the potential for drug toxicity.

A number of withdrawn drugs are known to undergo bioactivation by a range of drug metabolizing enzymes to chemically reactive metabolites that bind covalently to protein and DNA resulting in organ tox...

Clinical Trials [1064 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...

Investigation of the Effect of Short-term Orthokeratology With Increased Compression Factor on Ocular Parameters

Orthokeratology (ortho-k) is a clinical technique that uses reverse geometry rigid gas permeable contact lens exerting positive pressure on the central cornea to temporary reduce refractiv...

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...

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 1.6.99.2 (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 1.6.99.5 (NADH dehydrogenase (quinone)) requires NADH, is inhibited by AMP and 2,4-dinitrophenol but not by dicoumarol or folic acid derivatives. EC 1.6.99.6 (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.

Quick Search
Advertisement
 


DeepDyve research library

Relevant Topics

Hepatology
Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Pediatrics
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