Chemical Structure Determination of DNA Bases Modified by Active Metabolites of Lucidin-3-<i>O</i>-primeveroside

Ishii, Yuji; Okamura, Tomio; Inoue, Tomoki; Fukuhara, Kiyoshi; Umemura, Takashi; Nishikawa, Akiyoshi

doi:10.1021/tx900314c

Cited by 26 publications

(28 citation statements)

References 21 publications

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“…20,21 The objectives of this study are (1) to decipher the miscoding pattern of lucidin- N 2 -dG lesion during human TLS and (2) to gain mechanistic insight into such processes. To this end, we used our recently developed method to synthesize site-specifically modified oligodeoxynucleotides containing an LdG analogue.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ

Yockey¹,

Jha

Ghodke

et al. 2017

Chem. Res. Toxicol.

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DNA damage impinges on genetic information flow and has significant implications in human disease and aging. Lucidin-3-O-primeveroside (LuP) is an anthraquinone derivative present in madder root, which has been used as a coloring agent and food additive. LuP can be metabolically converted to genotoxic compound lucidin, which subsequently forms lucidin-specific N2-2′-deoxyguanosine (N2-dG) and N6-2′-deoxyadenosine (N6-dA) DNA adducts. Lucidin is mutagenic and carcinogenic in rodents but has low carcinogenic risks in humans. To understand the molecular mechanism of low carcinogenicity of lucidin in humans, we performed DNA replication assays using site-specifically modified oligodeoxynucleotides containing a structural analogue (LdG) of lucidin-N2-dG DNA adduct and determined the crystal structures of DNA polymerase (pol) κ in complex with LdG-bearing DNA and an incoming nucleotide. We examined four human pols (pol η, pol ι, pol κ, and Rev1) in their efficiency and accuracy during DNA replication with LdG; these pols are key players in translesion DNA synthesis. Our results demonstrate that pol κ efficiently and accurately replicates past the LdG adduct, whereas DNA replication by pol η, pol ι is compromised to different extents. Rev1 retains its ability to incorporate dCTP opposite the lesion albeit with decreased efficiency. Two ternary crystal structures of pol κ illustrate that the LdG adduct is accommodated by pol κ at the enzyme active site during insertion and postlesion-extension steps. The unique open active site of pol κ allows the adducted DNA to adopt a standard B-form for accurate DNA replication. Collectively, these biochemical and structural data provide mechanistic insights into the low carcinogenic risk of lucidin in humans.

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Section: Resultsmentioning

confidence: 99%

Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ

Yockey¹,

Jha

Ghodke

et al. 2017

Chem. Res. Toxicol.

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“…The resulting sulfate undergoes an elimination of HSO 4 -to produce QM 52. This latter molecule has been shown to react with DNA, thus, prompting carcinogenic effects [55] (see Table 3). …”

Section: Examples Of Chemically-derived Qmsmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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“…The chemical structures of Lu-specific 2′-deoxyguanosine (dG) and 2′-deoxyadenosine (dA) adducts following the reaction of dG and dA with the activated form of Luc determined by LC/MS showed two measurable adducts Luc-N 2 -dG and Lu-N 6 -dA, which were confirmed by NMR analysis 66) . To compare the adductome maps derived from MC-or Alz-induced DNA adducts with that of Luc-specific adducts, a comprehensive analysis of chemical-induced DNA adducts was performed on kidney DNA from rats treated for 8 weeks with diets supplemented with LuP, MC or Alz at concentrations of 0.3%, 5.0 or 0.8%, respectively.…”

Section: Modes Of Carcinogenic Actionmentioning

confidence: 82%

Possible Carcinogenic Mechanisms Underlying Renal Carcinogens in Food

Umemura

2014

Food Safety

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Some chemicals contained in foods originating from a variety of sources including natural plants, food additives, residual pesticides, mycotoxins and by-products created during food processing and/or cooking have previously been demonstrated to be carcinogenic at various sites in rodents. This review focuses on reported renal carcinogens in natural products such as d-limonene and aristolochic acid (AA), food additives such as potassium bromate (KBrO 3 ) and madder color (MC), as well as mycotoxins such as ochratoxin A (OTA) and citrinin (CTN) and discusses data from reporter gene mutation assays. In addition to in vivo genotoxicity, recent information on several factors related to chemical carcinogenesis, such as DNA modifications and cell proliferation, gave insight into possible modes of action that underlie renal carcinogenesis. Given that neither d-limonene nor CTN induced increases in mutant frequencies (MFs) in some reporter genes, cell proliferation at target sites arising from compensatory and/or direct mitogenic action may play a key role in the carcinogenic mechanism of these compounds. Clear positive results from reporter gene mutation assays for AA, MC and OTA strongly suggest that genotoxic mechanisms are involved in carcinogenesis induced by these agents. While KBrO 3 elevated MFs in the red/gam gene (Spi − ), it did so to a lower extent than did potent genotoxic carcinogens. Accordingly, the participation of genotoxic mechanisms in KBrO 3 -induced renal carcinogenesis may be limited.

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Chemical Structure Determination of DNA Bases Modified by Active Metabolites of Lucidin-3-O-primeveroside

Cited by 26 publications

References 21 publications

Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ

Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Possible Carcinogenic Mechanisms Underlying Renal Carcinogens in Food

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