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Influence of substrate complexity on the diastereoselective formation of spiroiminodihydantoin and guanidinohydantoin from chromate oxidation.

ABSTRACT: Chromate is a human carcinogen with a poorly defined mechanism of DNA damage. In vitro and prokaryotic studies have shown that DNA damage may occur via the formation of the hydantoin lesions guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) from further oxidation of 8-oxo-7,8-dihydroguanine (8oxoG). The unusual structure of these lesions coupled with their enhanced mutagenicity make them attractive for study with regard to their role in chromate-induced cancer. We have studied the formation of Gh versus Sp and their associated diastereomers following oxidation by model Cr(V) complexes and from in situ chromate reduction by ascorbate and glutathione. Identification of the two optically assigned diastereomers of Sp (R-Sp and S-Sp) as well as the two diastereomers of Gh (Gh1 and Gh2, not yet optically assigned) was carried out using increasingly sterically hindered substrates (nucleoside --> ssDNA --> dsDNA). Lesion formation and diastereomeric preference were found to be highly oxidant- and substrate-dependent. The Ir(IV)-positive control showed a shift from near equal levels of Gh and Sp and near equal levels of all four diastereomers in the nucleoside to all Gh formation in dsDNA, with a 5-fold enhancement in Gh2 over Gh1. The two model Cr(V) complexes used in this study, Cr(V)-salen and Cr(V)-ehba, showed opposite trends going from nucleoside to dsDNA with Cr(V)-salen giving enhanced Sp formation (with mainly R-Sp formed) and the Cr(V)-ehba having an oxidation profile nearly identical to that of Ir(IV). The two chromate reduction systems, Cr(6+)/ascorbate and Cr(6+)/glutathione, designed to model the intracellular reduction of chromate, showed lower levels of oxidation in all substrates. Notable in this group was the shift in the formation of the lesions to essentially all Sp for the Cr(6+)/ascorbate system with the most sterically hindered substrate, dsDNA. These results, when coupled with the known diastereomeric preference for excision of hydantoin lesions by the hNEIL1 enzyme, show the importance of defining both levels of lesion formation and diastereomeric preference of formation with regard to their potential impact on chromate carcinogenesis.

SUBMITTER: Gremaud JN

PROVIDER: S-EPMC2821960 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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Influence of substrate complexity on the diastereoselective formation of spiroiminodihydantoin and guanidinohydantoin from chromate oxidation.

Gremaud Julia N JN Martin Brooke D BD Sugden Kent D KD

Chemical research in toxicology 20100201 2

Chromate is a human carcinogen with a poorly defined mechanism of DNA damage. In vitro and prokaryotic studies have shown that DNA damage may occur via the formation of the hydantoin lesions guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) from further oxidation of 8-oxo-7,8-dihydroguanine (8oxoG). The unusual structure of these lesions coupled with their enhanced mutagenicity make them attractive for study with regard to their role in chromate-induced cancer. We have studied the formation ...[more]

PMID: 20014751

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Project description:OBJECTIVES:To analyse trends in the academic literature applying complexity science to healthcare, focusing specifically on bibliometric characteristics and indicators of influence. DESIGN:This study reports a bibliometric analysis via a systematic search of the academic literature applying complexity science to healthcare. METHOD:A search of four academic databases was performed on 19 April 2018. Article details were downloaded and screened against inclusion criteria (peer-reviewed journal articles applying complexity science to healthcare). Publication and content data were then collected from included articles, with analysis focusing on trends over time in the types and topics of articles, and where they are published. We also analysed the influence of this body of work through citation and network analyses. RESULTS:Articles on complexity science in healthcare were published in 268 journals, though a much smaller subset was responsible for a substantial proportion of this literature. USA contributed the largest number of articles, followed by the UK, Canada and Australia. Over time, the number of empirical and review articles increased, relative to non-empirical contributions. However, in general, non-empirical literature was more influential, with a series of introductory conceptual papers being the most influential based on both overall citations and their use as index references within a citation network. The most common topics of focus were health systems and organisations generally, and education, with recent uptake in research, policy, and change and improvement. CONCLUSIONS:This study identified changes in the types of articles on complexity science in healthcare published over time, and their content. There was evidence to suggest a shift from conceptual work to the application of concrete improvement strategies and increasingly in-depth examination of complex healthcare systems. We also identified variation in the influence of this literature at article level, and to a lesser extent by topic of focus.

Dataset Information

Influence of substrate complexity on the diastereoselective formation of spiroiminodihydantoin and guanidinohydantoin from chromate oxidation.

Publications

Influence of substrate complexity on the diastereoselective formation of spiroiminodihydantoin and guanidinohydantoin from chromate oxidation.

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