heavy metal mutagenicity: insights from bioinorganic model chemistry

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Journal of Inorganic Biochemistry 79 (2000) 261–265

Heavy metal mutagenicity: insights from bioinorganic model chemistry

Jens Muller, Roland K.O. Sigel, Bernhard Lippert *¨Fachbereich Chemie, Universitat Dortmund, 44221 Dortmund, Germany¨

Received 8 June 1999; received in revised form 26 August 1999; accepted 9 September 1999

Abstract

The mutagenicity of metal species may be the result of a direct interaction with the target molecule DNA. Possible scenarios leading tonucleobase mispairing are discussed, and selected examples are presented. They include changes in nucleobase selectivity as a consequenceof alterations in acid–base properties of nucleobase atoms and groups involved in complementary H bond formation, guanine deprotonation,and stabilization of rare nucleobase tautomers by metal ions. Oxidative nucleobase damage brought about by metal species will not beconsidered. q2000 Elsevier Science Inc. All rights reserved.

Keywords: Heavy metal mutagenicity; Bioinorganic model chemistry

1. Introduction

Mutagenesis is the result of spontaneous or induced basemispairing in DNA, hence a violation of proper Watson–Crick pairing undetected by the DNA repair machinery. Theoccurrence of rare nucleobase tautomers and/or a rotation ofthe nucleobase about the glycosidic bond to give syn rotamers(as opposed to the normal anti rotamers) has been implicatedin mispairing scenarios [1–4]. The existence of non-Watson–Crick base pairs, hence base pair mismatches, in syntheticDNA is firmly established today, as demonstrated in manyX-ray crystallographic [5,6] as well as NMR solution studies[7]. Without exception these mismatches include bases intheir preferred tautomeric structures, occasionally with basesin a syn orientation, with bases being protonated, or withsolvent (H2O) molecules included in the pair. There is onlyone example, intermolecular H bond formation between twoDNA hairpins, which appears to contain a pair between twothymine residues, one of which adopts a rare enol tautomerstructure [8].

Chemical modification of nucleobases, e.g. halogenation(5-bromouracil), alkylation (e.g. N(3) of purine bases orO(6) of guanine), or base cross-linking, to give these exam-ples only, is known to be responsible for mutations. Oxidativedamage of nucleobases or nucleotides, as brought about byreactive oxygen species or radicals in general, is commonlyconsidered another major reason of mutagenesis [9,10].

* Corresponding author. Fax: q49-231-7553797; e-mail: [email protected]

Metal species can be involved in the generation of reactiveoxygen species or, in a high oxidation state, directly oxidizenucleobases. NiII and CrO4

2y have been primarily studied inthis context [11,12]. At present there is no unified picture onmetal-induced mutagenicity, probably because differentpathways exist which can lead to mutagenesis. OxidativeDNA damage [9,10], interference with metal ions essentialfor DNA replication or transcription [13], impairment ofDNA repair processes [14], DNA cross-linking or DNAdistortion [15] may all lead to mutagenesis. In any case, adecrease in fidelity of DNA synthesis (replication) in thepresence of metal ions or metal coordination compounds iswell established [16]. As far as the mutagenicity of the anti-tumor agent cis-Pt(NH3)2Cl2 (cisplatin) is concerned, itappears not to be related to any redox chemistry. Rather ithas been suggested that it is the consequence of a replicativebypass of intrastrand 59-GpG and 59-ApG adducts [17], withan adenine misincorporated across the 59 base A [18] or G[19].

Our efforts to study basic aspects of metal–nucleobaseinteractions on a model-nucleobase level [20] has led us topursue also the question of processes that might lead to mis-pairing of bases or, more generally, to a prevention of properWatson–Crick pairing. In the following, selected exampleswill be presented and discussed.

2. Discussion

Among the various scenarios that could lead to mismatchformation between nucleobases as a consequence of metal

J. Muller et al. / Journal of Inorganic Biochemistry 79 (2000) 261–265¨262


coordination and could be studied on a model-nucleobaselevel, those affecting the nucleobase to be incorporated in thegrowing new strand or the template strand can be favorablymodeled. These include (at least)

i) blocking of H bonding sites,ii) cross-linking of nucleobases,

iii) effect on acid–base properties of H bonding sites,iv) effect on tautomer equilibrium,v) metal-induced hydrolysis of exocyclic base groups,

vi) hydrolysis of the glycosidic bond,vii) oxidative alterations of nucleobases,

viii) saturation of C–C double bonds in pyrimidine bases.As pointed out above, most of these possibilities do not

involve redox chemistry. In the following, only (iii) and (iv)will be discussed in more detail. Examples for (i) [21,22],(ii) [23,24], (vi) [25,26], (vii) [27–29] and (viii) [30]have been published or will be published (v). As far as metalsapplied in such studies are concerned, the use of kineticallyinert, diamagnetic species appears to be advantageous (eventhough not always biologically relevant) in that reactions caneasily be followed by NMR spectroscopy in solution andchances of isolating intermediates are generally better withkinetically inert species as opposed to labile ones. A point ofdifferentiation has to be made: In most cases metal ionsexhibit a charge effect which will pull electron density out ofthe heterocyclic ring, toward the metal. Exceptions to thisrule are those metal entities having strong back-donationproperties, and hence donate electron density from filled dorbitals into empty pU orbitals of the heterocycle, therebyovercompensating for the ordinary effect of a positivelycharged metal. RuII(NH3)5 is such an example [31,32],whereas the corresponding RuIII species behaves ‘normally’.In the following, only the ‘normal’ case will be considered.

2.1. Effects of metal coordination to acid–base propertiesof purine bases

Base–base recognition and hence proper Watson–Crickpairing crucially depend on charge densities within the het-erocyclic rings, pKa values of H donors as well as pKb valuesof H acceptors, and the tautomeric structures of the two bases[33]. From this it is evident that any chemical process affect-ing the complementarity of two bases, e.g. metal coordina-tion, will have an influence on the H bonding behavior.

PtII binding to N(7) of 9-methyladenine (9-MeA) reducesthe basicity of the N(1) position by 1.5–2.5 log units [34,35],and hence makes this site a weaker H bonding acceptor in theWatson–Crick pair with thymine. From a limited number ofdata points it appears that there is a minor influence of thecharge carried by the metal entity, e.g. [(NH3)3Pt]2q)

[(NH3)Cl2Pt])[PtCl3]y. It is to be expected that the metal

entity, while decreasing the basicity of N(1), simultaneouslyincreases the acidity of the exocyclic amino group, eventhough this effect cannot be determined accurately due to thehigh pKa of this group. The question of how these two oppos-ing effects influence the strength of the AT pair or whether

the pairing specificity of A is affected, remains elusive. Theproblem will be solved once metal complexes of A are avail-able that are sufficiently soluble in aprotic media such asCHCl3, etc., to permit the determination of associationconstants.

MII binding to N(3) of A with MsPt or Pd dramaticallydecreases the basicity of N(1) by more than 5 log units [36].Since it is unlikely that such a coordination mode wouldmarkedly increase the acidity of the exocyclic amino groupat the 6-position, it is tentatively concluded that a metal entitybound to N(3) of A will strongly weaken pair formationwith T.

Of course, metal binding to N(1) of A [23,37] blocks anyregular Watson–Crick pairing and therefore is not furtherdiscussed here. As far as Hoogsteen pairing is concerned,which involves N(7) and N(6), two opposing effects of themetal at N(1) are again operative, namely an increase ofN(6)H2 acidity, and a concomitant decrease of N(7)basicity.

Finally metal binding to N(6) of adenine, which can leadto a ‘metal-stabilized’ rare tautomer, will be discussed below.

The guanine-N(7) position is a preferred metal bindingsite. Experimental findings allow a quantification of the acid-ifying effect of a metal (e.g. CuII, NiII, PtII, PdII) [38]. Itamounts to an increase in pKa by 1.4–2.2 log units, with amaximum in the case of CuII. Auxiliary ligands bound to themetal have a modulating influence. As far as the two othergroups involved in Watson–Crick pairing with C are con-cerned, O(6) and N(2)H2, it is to be expected that the formerloses basicity and hence some of its H bonding acceptorproperties, whereas the amino protons at N(2) become some-what more acidic and hence will be better H donors. A quan-tification of the latter effects has not been achieved, however.

Experiments on the strength of the Watson–Crick pairbetween N(7) platinated G and free C, carried out in Me2SOand studied by concentration-dependent 1H NMR spectros-copy, have been conducted in a number of cases [39]. Ascompared to the Watson–Crick pairing in the absence of acoordinated metal ion [40], there is a remarkable increase inthe association constant of the Watson–Crick pair in the caseof a PtII entity located at N(7) of guanine. For example, inDMSO Kass for this pair is 6.9"1.3 My1, whereas it increasesto 13.0"2.0–16.3"4.0 My1 in the case of N(7) platinatedguanines. This increase in Kass has been predicted on the basisof theoretical calculations (gas phase, 0 K) [41–43], yet hasnot previously been determined experimentally. As far ascisplatin binding to double-stranded DNA is concerned, thisfinding suggests that the experimentally observed destabili-zation of DNA is not the consequence of a loss in H bondingcapacity but is rather due to other factors such as steric dis-tortion and loss of base stacking. What is important withregard to the established mutagenicity of 1,2-intrastrandadducts in 59-GpG [19] and 59-ApG [18] sequences is thatthere is an apparent loss in selectivity, meaning that theincrease in H bonding capacity of G upon platination alsotranslates into a higher affinity for non-complementary bases

J. Muller et al. / Journal of Inorganic Biochemistry 79 (2000) 261–265¨ 263


Scheme 4.

Scheme 3.

Scheme 2.

Scheme 1.

such as adenine. For example, a GA mispair could be formedif the 59 base is G which could result in a transversion muta-tion with GC converted into TA (Scheme 1).

2.2. Guanine–guanine mispairing

Neutral G and its N(1)-deprotonated form are self-com-plementary (Scheme 2). As a consequence, hemideproton-ated guanine is able to form a base pair consisting of three Hbonds. Such a base pair is expected to be primarily formedin a pH range that corresponds to the pKa of the deprotonationprocess. Whether it is of importance for guanine bases(pKa,9.5) is unknown. However, it definitely occurs withN(7)-methylguanine bases (pKa,7) [44,45] and, relevantto this discussion, for N(7) metalated (MsPtII) guanineentities (pKa,8) [46–50]. The pH argument for dimer for-mation should not be over-emphasized because experimen-tally it has been found that such GG pairs are also isolated atsubstantially lower pH values than 8. This situation is thus ina way reminiscent of hemiprotonated cytosine (‘i motif’[51,52]), which likewise exists at physiological pH despitea pKa of about 4.5 for protonated C.

Irrespective of the question of how easily a base incorpo-rated in DNA undergoes deprotonation [53], it needs to beemphasized that realization of such a GG mispair in duplexDNA is possible, in principle. X-ray crystallography on GGCtriplets in DNA triple helices has clearly established [54]that it is possible to have two Gs in an antiparallel stranddirection (as required for B-DNA) with (i) a transoid ori-entation of the glycosidic bonds and (ii) an anti sugar ori-entation of both bases (Scheme 3(a); GG part shown only).If one of the bases were to be metalated and deprotonated, asimple rotation of the second G about the glycosidic bond(anti™syn) would be required to generate such a GGmispair(Scheme 3(b)).

2.3. Metal binding and nucleobase tautomerism

There are two principal ways of influencing nucleobasetautomerism by a metal entity: (i) The metal is bonded to asite not involved in Watson–Crick hydrogen bond formation,e.g. N(7) or N(3) of a purine base, yet affecting the tautomerequilibrium. We have attempted to prove such a scenario inthe case of adenine by application of the ‘method of basicitymeasurements’ [34]. As we have pointed out, this methoddoes not provide an unambiguous answer to the question,even though the assumption of the influence of the tautomerequilibrium makes sense from a chemical point of view.Moreover, the postulated mispair between a N(7) platinatedrare adenine tautomer and a normal adenine tautomer (in synorientation) would be in agreement with the observedAT™TA transversion caused by the d(ApG) adduct of cis-platin [18]. (ii) The metal replaces a proton involved in theproper tautomeric structure and ‘forces’ this proton to takeanother site. As a result a ‘metal-stabilized’ rare nucleobasetautomer is formed. In that case, the rare tautomer as its metaladduct can be isolated quantitatively! This principle can beapplied to all four bases of DNA or RNA, and X-ray crystalstructure analyses confirm this scenario (Scheme 4). Forexample, replacing the proton at the N(3) position of T or Uby a metal entity and shifting the proton to O(4) gives themetalated form of the rare 2-oxo,4-hydroxo tautomer of thesebases [55–57]. Similarly, metal binding to N(1) of G andproton shift to N(7) (or O(6)) [58] produces metalated

J. Muller et al. / Journal of Inorganic Biochemistry 79 (2000) 261–265¨264


forms of (two different) rare tautomers of this base. In thecase of C and A, protons of the exocylic amino groups needto be exchanged by metal entities and the substituted protonis shifted to N(3) (of CU) or N(1) (of AU), respectively,resulting in metalated forms of the iminooxo tautomer ofcytosine and the imino tautomer of adenine. A complicatingfactor is that there is the possibility of rotation of the metalentity about the C–N bond of the exocyclic group.

In the following, metal-stabilized adenine and cytosine raretautomer forms are briefly discussed. Metal coordination tothe exocyclic amino group of A, with replacement of one ofthe N–H protons, has been reported in a number of cases [59–65]. Among them are those patterns of particular interestwith regard to the mutagenicity aspect that leave the pyrim-idine part of the base, specifically N(1), available for H bondformation and protonation. Three examples apply to this sit-uation: a dinuclear MoII complex, with metal ions at N(7)and N(6) [63], a HgII complex [64], and to some extentalso a PtII complex [65] even though the protonation siteN(1) or N(7) is ambiguous. While in the first two cases themetal is anti with respect to the N(1) site and hence does notsterically interfere with H bonding at the pyrimidine entity,the (dien)PtII moiety in the third case is oriented syn, butsolution NMR spectra indicate an equilibrium between synand anti. The syn orientation of the metal entity inevitablyprevents proper Watson–Crick pairing for steric reasons andthe anti orientation does not permit it, provided the N(1)position is protonated, as is the case of the [MoII]2 and HgII

compounds. As pointed out by Clarke [59] and Arpalahtiand Klika [65], the pH and hence the protonation state of theA base have an effect on the orientation of the metal entity.Theoretical calculations [66] strongly suggest that N(6)metal binding inherently favors N(1) protonation, and hencethe formation of a metal-stabilized rare tautomer. This sug-gests that mispairing scenarios of N(6) metalated adeninebases with either G (syn), leading eventually to a transversionmutation (AT™CG), or with C (anti), leading to a transi-tion mutation (AT™GC), are viable possibilities [64].

The situation with N(4) metalated C is very similar to thatof N(6) metalated A: Metal binding to this site causes a shiftof the amino proton to N(3) and hence generates the rareimino tautomer of C. Depending on the pKa value of theproton at N(3), it may be lost. Examples of either case areknown, e.g. for RuII [67], RuIII [59], HgII [68], PtIV [69]and PtII [70–72]. This list does not contain examples ofmultiple metal binding patterns, which include N(4) amongother sites, e.g. N(3) [73], or N(4),N(3) chelation [62].In the case of PtII binding to N(4) the mechanism of forma-tion involves several PtIV species [69–72]. As far as potentialmispairing patterns of the rare tautomer are concerned, it willdepend on the orientation of the metal entity (syn or anti withrespect to N(3)) and the protonation state of N(3), whichmispairs are feasible [70]. Of the various mismatchesbetween C and A, predicted or actually observed [74], andcontaining at least two H bonds, none would appear to be

favored (or even possible) in the case of the N(4) metalatedrare C tautomer [70].

3. Summary

Scenarios have been outlined as to how metal entities bind-ing to nucleobases in DNA might result in the formation ofmispairs which, if not repaired, could lead to point mutations.Only non-redox processes have been considered. Our presentunderstanding of the mutagenic potential of cisplatin clearlysupports the option that metal-related mutagenicity can arisefrom mispairing of metalated bases. However, we are awarethat additional scenarios are feasible. For example, it has beensuggested that an error-prone response to substitution-inertmetal ions in bacterial DNA could also be the reason formutagenicity [75].

Acknowledgements

Financial support of this work from the DFG and FCI isgratefully acknowledged. R.K.O.S. wishes to thank the SwissNational Science Foundation and the Swiss Federal Officefor Education and Science for a TMR-fellowship (No. 83EU-046320) and J.M. thanks the Land Nordrhein-Westfalenfor a fellowship. This work was also part of a COST-D8collaboration with the group of H. Sigel, Basel, Switzerland.

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heavy metal mutagenicity: insights from bioinorganic model chemistry

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