Photochemical DNA modifications induced by 1,2-dioxetanes

Epe, Bernd; Müller, Elvira; Adam, Waldemar; Saha‐Möller, Chantu R.

doi:10.1016/0009-2797(92)90067-u

Cited by 30 publications

(26 citation statements)

References 39 publications

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“…8oth findings can be explained by the assumption that in the case of furocoumarin 4a -60% of the FPG-sensitive modifications are generated via a direct electron transfer or hydrogen abstraction (type I) reaction with DNA, which is not affected by t-butanol and yields only few strand breaks and AP sites. The formation of FPG-sensitive modifications (8-hydroxyguanine) by type I reactions has been demonstrated recently (35)(36)(37). The small extent of DNA darnage caused by the corresponding alcohol4b then indicates that the hydroperoxide moiety is also important for this damaging mechanism.…”

Section: Discussionmentioning

confidence: 99%

DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm)

et al. 1993

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Wben irradJated at 360 nm, furocoumarins wfth a hydroperoxide group in a side chain ef6ciently give rise to a type of DNA darnage that can best be explained by a pbot. induced generation of hydroxyl radleals from the excited pbotosensitizers. The observed DNA darnage profiles, i.e. the ratios of single-strand breaks, sites of base loss (AP sites) and base modifications sensitive to fonnamidopyrlmidine-DNA glycosylase (FPG protein) and endonuclease m, are similar to the DNA darnage protile produced by hydroxyl radicals generated by lonizing radiation or by xantbine and xanthine oxidase in the presence of Fe(III)-EDTA. No such darnage is observed with the correspond.ing furocoumarin alcohols or in the absence of near-UV radiation. The darnage caused by the photo-excited bydroperoxides is not influenced by superoxide dismutase (SOD) or catalase or by DzO as solvent. Tbe presence of t-butanol, however, reduces both the formation of single-strand breaks and of base modifications sensitive to FPG protein. Tbe cytotoxicity caused by one of the hydroperoxides in L5178Y mome Iymphoma ceJis is found to be dependent on the near-UV Irradiation and to be much higher than that of tbe corresponding alcohol. Tberefore the new type of phot.induced darnage occurs inside cells. lntercalating photosensitizers with an attached hydroperoxide group might represent a novel and versatile class of DNA damaging agents, e.g. for phototherapy. lntroduction Upon excitation by visible light or near-UV radiation many photosensitizers induce oxidative DNA damage, eitb.er indirectly via singlet oxygen (type II reaction) or directly via hydrogen abstraction or electron transfer (type I) reaction with DNA (1-6).The spectrum ofDNA modifications generated by these reactions is very different from that induced by hydroxyl radicals. Wbile hydroxyl radicals (e.g. generated by ionizing radiation or by Superoxide in the presence of Fe(lß)-EDT A) induce approximately equal amounts of base modifications (7), singlestrand breaks and sites ofbase loss (AP sites), both singlet oxygen and several photosensitizers in the presence of light generate predominantly base modifications (8-10). Some (or all) of the base modifications are recognized by the repair endonuclease fonnamidopyrimidine-DNA glycosylase (FPG protein) (8-10).At least some of these FPG-sensitive base modifications have been identified as 8-hydroxyguani.ne (7.~y~8-oxoguanine) (11,12 SSB+ ESS=-ln{l.4 x//(1.4 X/+11)) {I)wbere I is the ftuorescence of tbe supercoiled form and II is the fluorescence of tbe relaxed form.

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Section: Discussionmentioning

confidence: 99%

DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm)

et al. 1993

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“…Tri- and tetramethyl dioxetane produce more CPDs than do dioxetanes having larger substituents and higher triplet state energies [47, 48]. Larger substituents instead tend to produce DNA strand breaks, dihydropyrimidines, abasic sites, and 8-oxo-guanine or ring-opened purines, apparently reflecting the dominance of H or e − abstraction over Dexter energy transfer.…”

Section: Consequences Of Excited Statesmentioning

confidence: 99%

Chemical excitation of electrons: A dark path to melanoma

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2016

DNA Repair

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Sunlight’s ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In pigmented melanocytes, we found that CPDs arise both instantaneously and for hours after UV exposure ends. Remarkably, the CPDs arising in the dark originate by a novel pathway that resembles bioluminescence but does not end in light: First, UV activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX), which generate the radicals nitric oxide (NO•) and superoxide (O2•−); these combine to form the powerful oxidant peroxynitrite (ONOO−). A fragment of the skin pigment melanin is then oxidized, exciting an electron to an energy level so high that it is rarely seen in biology. This process of chemically exciting electrons, termed “chemiexcitation”, is used by fireflies to generate light but it had never been seen in mammalian cells. In melanocytes, the energy transfers radiationlessly to DNA, inducing CPDs. Chemiexcitation is a new source of genome instability, and it calls attention to endogenous mechanisms of genome maintenance that prevent electronic excitation or dissipate the energy of excited states. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.

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“…. fold increase of the dioxetane-induced FPG-sensitive base modifications was observed in D 2 0 vs. H 2 0 as solvent [15]~ indicates that singlet oxygen plays a certain role in the formation of FPG protein-sensitive lesions, but is not a mandatory intermediate~ otherwise a much higher 0 2 0 effect would have been observed.…”

Section: Genotoxicity In She Cellsmentioning

confidence: 94%

“…However, only a small fraction ofthe base modifi~ cations consisted of pyrimidine dimers, as established by employing a specific UV endonuclease preparation from Micrococcus luteus (14]. Most recent results [15] reveal that the majority of the dioxetane-promoted endonuclease-sensitive base modifi-43 cations in PM2 DNA are recognized by FPG protein (formamidopyrimidine-DNA glycosylase ). Since the FPG protein recognizes both the 7 ,8-dihydro-8-oxoguanine (8-oxoGua) and formamidopyrimidines (Fapy), these are presumably the major DNA lesions responsible for the observed DNA damage.…”

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Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells

et al. 1993

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SUMMARY1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase-activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212 Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system.

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Photochemical DNA modifications induced by 1,2-dioxetanes

Cited by 30 publications

References 39 publications

DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm)

DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm)

Chemical excitation of electrons: A dark path to melanoma

Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells

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