Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450.

Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Research Abstract Details 

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Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Abstract Text:

Naiyu Zheng,Shaokun Pang,Tomoyuki Oe,Carolyn A Felix,Suzanne Wehrli,Ian A Blair,

Etoposide (VP-16), a DNA topoisomerase II poison widely used as an antineoplastic agent is also known to cause leukemia. One of its major metabolic pathways involves O-demethylation to etoposide catechol (etoposide-OH) by cytochrome P450 3A4 (CYP3A4). The catechol metabolite can undergo sequential one- and two-electron oxidations to form etoposide semi-quinone (etoposide-SQ) and etoposide quinone (etoposide-Q), respectively, which have both been implicated as cytotoxic metabolites. However, etoposide-Q is known to react with glutathione (GSH), which can protect DNA from oxidative damage by this reactive metabolite. In this study, etoposide-Q was reacted with GSH and the two etoposide-GSH conjugates were characterized. The major conjugate was etoposide-OH-6'-SG and the minor product was etoposide-OH-2'-SG. Etoposide-OH-6'-SG, which arose from Michael addition of GSH to etoposide-Q, was characterized by mass spectrometry and 2-D NMR. It was identified as the sole product from in vitro metabolism experiments using recombinant human CYP3A4 or liver microsomes incubated with etoposide in the presence of GSH. Etoposide-OH-6'-SG was also detected from incubations of etoposide-OH and GSH alone. Therefore, the presence of etoposide-OH, which can be formed from etoposide metabolism by CYP3A4, is essential for formation of the GSH conjugate. The oxidation of etoposide-OH to a quinone intermediate is likely the precursor in the formation of etoposide-OH-6'-SG.

Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Publishing Authors By Initials

N Zheng,S Pang,T Oe,CA Felix,S Wehrli,IA Blair,

For similar cells: cellular structures: subcellular fractions: microsomes: microsomes, liver research abstracts see: cells: cellular structures: subcellular fractions: microsomes: microsomes, liver research

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Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Current drug metabolism

VOLUME: 7

Page Numbers: 897-911

Journal Abbreviation: Curr. Drug Metab.

ISSN: 1389-2002

DAY: 3

MONTH: Dec

YEAR: 2006

Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 100960533

Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Keywords Mesh Terms:

KEYWORDS: Microsomes, Liver

MESH TERMS: metabolism

Chemical & Substance for Abstract: Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450. Information

Substance Name: CYP3A4 protein, human

Registry Number: EC 1.14.13.67

Grant and Affiliation Information for Characterization of an etoposide-glutathione conjugate derived from metabolic activation by human cytochrome p450.

AFFILIATION: Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, 854 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.

Country: Netherlands

AGENCY: United States NCI

GRANT: CA 80175

ACRONYM: CA

MEDLINETA: Curr Drug Metab

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