Reaction kinetics of 4-methoxy ortho benzoquinone in relation to its mechanism of cytotoxicity: a pulse radiolysis study.

2.50
Hdl Handle:
http://hdl.handle.net/10541/109770
Title:
Reaction kinetics of 4-methoxy ortho benzoquinone in relation to its mechanism of cytotoxicity: a pulse radiolysis study.
Authors:
Land, Edward J; Cooksey, C J; Riley, P A
Abstract:
Rate constants quantifying the reactivity of 4-methoxy ortho benzoquinone, formed in the metabolic activation of 4-hydroxyanisole, a possible melanocytotoxic drug under current assessment as a treatment for malignant melanoma, have been determined by pulse radiolysis. The quinone is reactive towards the thiols cysteine (k = 3.5x10(5)M-1sec-1), glutathione (k = 3.1x10(5)M-1sec-1) and dithiothreitol (k = 3.5x10(5)M-1sec-1), but relatively unreactive towards other nucleophiles such as arginine (k less than or equal to 1M-1sec-1) and glutamine (k less than or equal to 1M-1sec-1). Redox exchange with ascorbate also occurs (k = 1.0x10(4)M-1sec-1). In view of the low reactivity of 4-methoxy ortho benzosemiquinone towards oxygen (k less than or equal to 10(5)M-1sec-1) and the model lipid trans-2-butenoic acid (k less than or equal to 2x10(5)M-1sec-1), it is unlikely that initiation of lipid peroxidation by the semiquinone is a major source of cytotoxicity. A more likely toxicity pathway appears to be covalent addition reactions of 4-methoxy ortho benzoquinone with cellular nucleophiles, especially thiols, and/or redox exchange reactions of the quinone leading to antioxidant depletion.
Affiliation:
Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, U.K.
Citation:
Reaction kinetics of 4-methoxy ortho benzoquinone in relation to its mechanism of cytotoxicity: a pulse radiolysis study. 1990, 39 (6):1133-5 Biochem. Pharmacol.
Journal:
Biochemical Pharmacology
Issue Date:
15-Mar-1990
URI:
http://hdl.handle.net/10541/109770
DOI:
10.1016/0006-2952(90)90294-U
PubMed ID:
2322299
Type:
Article
Language:
en
ISSN:
0006-2952
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLand, Edward Jen
dc.contributor.authorCooksey, C Jen
dc.contributor.authorRiley, P Aen
dc.date.accessioned2010-08-17T13:40:53Z-
dc.date.available2010-08-17T13:40:53Z-
dc.date.issued1990-03-15-
dc.identifier.citationReaction kinetics of 4-methoxy ortho benzoquinone in relation to its mechanism of cytotoxicity: a pulse radiolysis study. 1990, 39 (6):1133-5 Biochem. Pharmacol.en
dc.identifier.issn0006-2952-
dc.identifier.pmid2322299-
dc.identifier.doi10.1016/0006-2952(90)90294-U-
dc.identifier.urihttp://hdl.handle.net/10541/109770-
dc.description.abstractRate constants quantifying the reactivity of 4-methoxy ortho benzoquinone, formed in the metabolic activation of 4-hydroxyanisole, a possible melanocytotoxic drug under current assessment as a treatment for malignant melanoma, have been determined by pulse radiolysis. The quinone is reactive towards the thiols cysteine (k = 3.5x10(5)M-1sec-1), glutathione (k = 3.1x10(5)M-1sec-1) and dithiothreitol (k = 3.5x10(5)M-1sec-1), but relatively unreactive towards other nucleophiles such as arginine (k less than or equal to 1M-1sec-1) and glutamine (k less than or equal to 1M-1sec-1). Redox exchange with ascorbate also occurs (k = 1.0x10(4)M-1sec-1). In view of the low reactivity of 4-methoxy ortho benzosemiquinone towards oxygen (k less than or equal to 10(5)M-1sec-1) and the model lipid trans-2-butenoic acid (k less than or equal to 2x10(5)M-1sec-1), it is unlikely that initiation of lipid peroxidation by the semiquinone is a major source of cytotoxicity. A more likely toxicity pathway appears to be covalent addition reactions of 4-methoxy ortho benzoquinone with cellular nucleophiles, especially thiols, and/or redox exchange reactions of the quinone leading to antioxidant depletion.en
dc.language.isoenen
dc.subjectAnticancerous Agentsen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBenzoquinones-
dc.subject.meshChemical Phenomena-
dc.subject.meshChemistry-
dc.subject.meshKinetics-
dc.subject.meshOxidation-Reduction-
dc.subject.meshPulse Radiolysis-
dc.subject.meshQuinones-
dc.titleReaction kinetics of 4-methoxy ortho benzoquinone in relation to its mechanism of cytotoxicity: a pulse radiolysis study.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, U.K.en
dc.identifier.journalBiochemical Pharmacologyen

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