Molecular analysis of mutations induced by the intercalating agent ellipticine at the <i>hisd3052</i> allele of <i>salmonella typhimurium</i> TA98

DeMarini, David M.; Abu‐Shakra, Amal; Gupta, Ranjan; Hendee, Linda J.; Levine, Jessie G.

doi:10.1002/em.2850200104

Cited by 35 publications

(26 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, mutagenicity of ellipticines should be evaluated as a potential risk factor for these anticancer agents. Most ellipticines are mutagenic to Salmonella typhimurium Ames tester strains, bacteriophage T4, Neurospora crassa, and mammalian cells and induce prophage lambda in Escherichia coli 10 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

View full text Add to dashboard Cite

Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy-and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N 6 of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy-and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP-and peroxidase-mediated metabolite, ellipticine N 2 -oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

show abstract

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

View full text Add to dashboard Cite

show abstract

“…The formation ofmany ofthe complex mutations in TA98 are compatible with mutation models that involve the misinsertion of a base opposite a DNA adduct followed by slipped mispairing (28). Perhaps the most important feature ofthe hisD3052 target is the quasipalindromic nature of its sequence, i.e., the fact that it contains many direct and inverted repeated sequences.…”

Section: Mutational Mechanismsmentioning

confidence: 70%

“…DNA secondary structures and these mechanisms appear to account for a great majority of the mutations recovered among revertants of the hisD3052 allele (19)(20)(21)(22)(23)28). Similar mechanisms also explain mutations recovered from a variety of other organisms, including humans (43).…”

Section: Mutational Mechanismsmentioning

confidence: 89%

“…When a secondary structure of this region is constructed that contains 66% internal hydrogen bonding, the two warm spots reside opposite each other in loopedout (nonhydrogen-bonded) regions of the hairpin (28). Such mutational specificity has not been observed among the other agents we have studied thus far.…”

Section: Mutation Spectra Produced By Single Chemicalsmentioning

confidence: 89%

“…In addition, the CGCGCGCG region may assume a Z-DNA conformation, which could promote deletion mutations. These mechanisms have been discussed extensively by us and others (19)(20)(21)(22)(23)28).…”

Section: Mutational Mechanismsmentioning

confidence: 97%

See 2 more Smart Citations

Molecular analysis of mutations induced at the hisD3052 allele of Salmonella by single chemicals and complex mixtures.

DeMarini

Bell

Levine

et al. 1993

Environ Health Perspect

View full text Add to dashboard Cite

More single chemicals and complex environmental mixtures have been evaluated for mutagenicity at the hisD3052 allele of Salmonella, primarily in strain TA98, than in any other mutation assay. The development of colony probe hybridization procedures and the application of the polymerase chain reaction and direct DNA sequencing has permitted rapid molecular access to this allele. We discuss these techniques and the resulting mutation spectra that have been induced by a variety of environmental mutagens and complex mixtures. A common GC or CG deletion within a hot-spot region of the sequence dominates most of the spectra. In addition to this two-base deletion, we have recovered about 200 other types of mutations within the 72-base target for reversion of the hisD3052 allele. These include a variety of deletions (as large as 35 bases), duplications (as large as 46 bases), and complex mutations involving base substitutions. The quasipalindromic nature of the target sequence and its potential to form DNA secondary structures and slippage mismatches appear to be an important basis for the mutability of this allele.

show abstract

Synthesis of polyaniline using horseradish peroxidase immobilized on plasma‐functionalized polyethylene surfaces as initiator

Álvarez

Manolache

Dénès

2003

J of Applied Polymer Sci

View full text Add to dashboard Cite

ABSTRACT:The doping of semiconducting conjugated polymers (e.g., polyaniline, PANI) can result in the elimination of the bandgap, leading to high electrical conductivities (comparable to metals). Doped PANI is totally insoluble and thus nonprocessable, which considerably limits its practical applications. Synthesis of PANI using immobilized horseradish peroxidase (HRP) as a catalyst in aqueous solutions can open up additional possibilities for applications through the direct synthesis of controlled-thickness PANI layers on various substrate surfaces. The RF plasma-enhanced surface functionalization of polyethylene and the covalent immobilization of HRP are discussed, and the polymerization of aniline initiated by immobilized HRP is presented. The nature of plasma-grafted surface functionalities on the substrate surfaces and the formation of PANI are demonstrated using X-ray photoelectron spectroscopy and attenuated total reflectance Fourier transform IR spectroscopy. The molecular weight distribution of PANI is evaluated with gel permeation chromatography, and the activity of the immobilized enzyme is monitored using UV spectroscopy.

show abstract

Molecular analysis of mutations induced by the intercalating agent ellipticine at the hisd3052 allele of salmonella typhimurium TA98

Cited by 35 publications

References 45 publications

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Molecular analysis of mutations induced at the hisD3052 allele of Salmonella by single chemicals and complex mixtures.

Synthesis of polyaniline using horseradish peroxidase immobilized on plasma‐functionalized polyethylene surfaces as initiator

Contact Info

Product

Resources

About