Document e74vqGV4gVvye4gdwzXzDqQEq

Br. J. Cancer (1981) 44, 397 Letter to the Editor MECHANISMS OF VINYL CHLORIDE CARCINOGENICITY/MUTAGENICITY Sik,--The present letter sots out to show that the various deoxyribonucleoside (and ribonucleoside) analogues, which have been isolated from the chemical, non-enzymic reaction (Hathtvay, 1980) between the ulti mate vinyl chloride metabolites and targetorgan DXA (and RXA) components in vivo, appear to be biologically significant and com patible with ensuring mutagenicity and carcinogenicity. Thus, Green & Hathway (1978) (see also Hath way, 1977) produced strong evidence in the form of published mass fragmentograms for the presence of the imidazo-cyelization products of dcoxyadenosinc (dA) and deoxyevtidine (dC) (viz. 9-(/8-D-2'-deoxj'ribofuranosyl)imidazo[2.1-i]purine (etheno-dA) and 1 - {j8-D-2'-deoxyribofuranosyl)imidazo|T.2-e]pyrimid-2(lH)-one (etheno-dC)) in chromato graphic fractions of the. enzymic hvdrotysatos of the modified liver DXA of surviving rats which had been exposed chronically to long term vinyl chloride in their drinking water (250 pt/106). Out of the large group of animals which had been exposed to vinyl chloride in this way. there was a high incidence of rats that died with liver haemangiosarcotna (I.A.li.G. Monographs, 1979) during the. 2-year experiment, it was implicitly inferred (Green & Hathway, 1978) that these results indicated a causal relationship; i.e. that forma tion of ethnno-dA and etheno-dC may repre sent pro-mutagenic lesions in the extra-hepa tocellular liver-tissue DXA of animals exposed to vinyl chloride. Furthermore, formation of etheno-dA and ctheno-dC in vivo and in model experiments of the reaction of vinyl chloride-derived -ehloroethvione oxide or its rearrangement product, ehloroucetaldohyde, with calf-thymus DXA implied a common reaction mechanism. In both cases (Fig. 1), initial (S,\-2) alkylation occurred at the most nucleophilic ring-nitrogen (Ar-I of the dA residues and N-3 of the dC ones), followed successively by loss of the elements of water with ring-closure between the oxo-group and the amino-group belonging to C-6 of the dA residues (and of C-4 of the dC ones) and by proton loss (Hathway & Kolar, 1980). At the same time as the foregoing, Laib & Bolt (1977, 1978) provided chromatographic evidence for the presence of the correspond ingly modified ribonucleosides in fractions of the enzymic hydrolysate of the liver RXA of rats which had been exposed to a large, single radioactive dose, of 14G-vinyl chloride, and they confirmed their results with incubations of rat-liver mierosomes, 1JC-vinvl chloride and the. appropriate polynucleotide, fortified with XADPH. From the time-course experi ments, these authors (1978) showed relative persistence, of etheno-C compared with etheno-A in rat-liver DXA, suggesting its greater biological significance. They com mented on the contrast between the pattern of RXA nucleoside analogues and that of DXA in which the dG residues (see below) were said to be the principal target for alkylation, but they have not published their experimental evidence. At that time too, Osterman-Golkar el al. (1977) showed the chromatographic separa tion, after XaBH.j treatment, of 7-X-(2hydroxycthyljguanine from the acid hydro lysate of the liver DXA of mice, exposed acutely to 14C-vinyl chloride, anti they V^NH, +cr +h2o dR + H+ Fm. 1. 40 EC- 1702 5 OS um'iiii to Tin-: ivuitou attributed this result to formation of 7-Ar-(2oxocthyl)dG residues, but they did not look in their DMA hydrolysates for etheno-dA and othcno-dC, winch, on account of the method of exposure, may have been absent from their material or below the limits of detection. (Subsequently. Bolt et al. (1981) suggested that the Swedish workers' aldehyde may exist as a (i-membered cyclic hemi-acetal (Fig, 2) in DXA. Consideration of molecular models show: (i) that the imidazole ring in vinyl chloride nucleoside analogues is co-plannr or almost co-planar with the rest of the molecule, and this observation finds support in X-ray crystallography (Wang el ul.. 1974. 197(jj: (ii) that the imidazole ring in these nucleoside analogues shields 2 normal hydroge.iilumding positions (Hathwav & Kolar, 1980): (iii) that in the case of ethcno-dC (or ethenoC), the second ring confers on the cytosine residue the dimensions of adenine, with the result that otheno-dC would he expected to simulate dA nucleosidcs/nueleotides in repli cation (Hall el ul., 1981; Barhin el ul., 1981) and etheno-C the A ones in transcription (Spongier & Singer, 1981); (iv) that the misincorporation envisaged in these biological processes would he facilitated by complex, formation involving base pairing (Fig. 3) of protonatod molecular species, which were invoked (Topal & Fresco, 197G) to extend the Watson-Crick concept for complementary base pairing; (v) that the relatively bulky imidazole ring resembles an alkyl substituent and effectively blocks one of the available base-pairing sites. When DXA-like polymers, po)y(dA-dT) and poly(dC-dG), that were pre-treated with ehloroacetaldehyde, were used as templates for E. coli DXA polymerase 1 in an in vitro assay (Hall et al.. 1981) replication was decelerated, and increased levels of non complementary nucleosides were incorpor ated. (Although DXA repair has never been studied per .se. it is not entirely ignored in this work, as DXA polymerase 1 belongs to the repair system.) With the modified (dA-dT) templates. 1 dGMP was incorporated for every -- Of I etheno-dA residues present, hut no misincorporation of dCMP occurred, and with the poly(dC-dG) templates. 1 misincor poration of dAMP or dTMP occurred respect ively in the presence of *-30 or 80 e.thono-dC residues. Thu principal miscodings of ctheno- Fig. 3. TETTER TO 'J'HE EDITOR 59!) ,1 to 11'pli- IS1) (iou ittisgiCill jik'X.'!) of .i ore i the it ary ulky . uent , la hie \-ilT) with dA may represent a potential pro-mutiigcnic (107S) New observations concerning the cliloro- lesion, which would he expected to lead to acetaldehyde reaction wit it sumo tRNA eon* (dA-dT)-(dC-dfT) trainversions, and simi stituents, .-.table intermediates, kinetics and selcerivifv of tho reaction. *Yitelcic Avid# Jics.t 5, ) i larly those of ctheno-dC would possibly induce (dC-dO)-(dA-dT) trailsversions. Neure't-neitfhhour analysis with modified poly- 789. Bolt, H. M., Filnkx, .7, 0. & Laio, K. J. (Hhsl) Com ulent binding of baloethyieno,s. 2n<7 Ini. (dC-dG) templates showed that 00% of the St/ntf). Hiofayivnl Practice Intermediates. Kd. Snyder et al. Xcw York: Plenum Press. (In press). inisineorporations, of say A. occurred opposite Giiekn, T. & HatuwaY, D. K. (1978) Jnternetions of cytosine (or etheno-cytosinc). hut a small vinyl chloride with rat-liver DXA in vivo. Client. number of errors (--10%) occurred opposite guanine bases, which may he due to the sus pected formation of the cyclic, hcmi-acctal of Hiol. Interact,, 22, 21 L Hall, J. A., Sakkuill. R,, Guides, T. it Hatiiwav, D. K. (1981) The induction of errors during in vitro DXA synthesis following chlomaectaldchydc- <10 (Fig, 2) in the modified pnly(dC-dG) tem treatment of poly(dA-dT) and polv(dC-dG) tem plates. However, work on the kinetics and selectivity of the reaction of chloroacctaldclivdc with some tRNA constituents shows plates. Cnrcinor/encvi#. 2, Ml. Hatuway. J), E. (M)77) Comparative mammalian metabolism of vinyl chloride and vinyljdene chloride m relation to oncogenic potential. that it is probable that no nucleoside ana Environ. limlth Perspect.. 21, 55. liltCS I'ilro was uoti- logues other than the imidazo-cyclization products are formed (Bicrnat et al., 1078). Induction of (dA-dT)-(dC-dG) and (dCdG)-(dA-dT) transversions from etheno-dA Hatuway, D. K. (1989) The1 importance of (nonenzymic) cliemical reaction processes to the fate of foreign compounds in mammal*. Chcm, Noe. Her., 9, o:;. Hatuway, 1). E. 8:- Koi.au, CL F. (1980) Mechanisms ')iorhcen : this the \-.lT) ! for Imt and ncor , ieet .o-dC arno- and ctheno-dC' an! consistent with the fact that ehloroethylene oxide, chloroncetaldehyde and metaholieally activated vinyl chloride induce hase-pair-suhstitution mutations (Rannug el al.. 1074: Malaveille et al.. 1075; IdeGann el ul.. 1075; Phillips et al.. 1980), hut not frame-shift mutations, in Salmonella Ujphlmunum strains. It follows that the mechanism of vinyl chloride carcinogenicity/ mutagenicity has been studied more intens ively than that of any other human carcin ogen. of reaction between the ultimate chemical carcino gens ami nucleic aod, t'hnn. Sor. 9, 241. SAftV Monof/rnfifis (1979) On lhe iicuhnition of thr. ('/trr/nof/cnir /lislw of (.hctn'n-ttU fo Jhnn/tn*. Some nuniomers, plastich ami synthetic elastomers, and acrolein, fnt, Arjnny lies, {'oncer. 19, `177. La in, R. J, & Bolt, H. M. (1 !I77) Aik v latum of KXA by \ mvl chloride metabolites in vitro and in vivo: Formation of J ,A`"-cthenuudonoMiie. TofieoUnji/, 8, 185. La in. K. J. <t Bolt, H, M. (1978) Formation of .'L.V^-ethenoe.ytidine moieius m KXA by vinyl chloride metabolites in vitro and nt vh'O. Arch. To.rirol., 39, 235. McC'avx, )., Sim.mov. V., Stuf.itu ikslu, D. & D. K. Hath wav 7.6'./. Limited. Central To.ricolnt/i/ Laboralanj, AUlerley Park. Cheshire. SKK) 47V. Amis, B. X'. (1975) Mutagenicity of chlor* acetaldt'liyde, a possible metabolic product of 1,2-<(icldoroi't !miH% ehloroetItanol, \'inyl chloride and cyclophosphamide. Prov. A'atl Acad. Sci.. r.N.A.,73, 3190. Malavbilus, C.. JlAHTsrir. H.. Bakuin, A., (`ami's. During our attack on the vinyl chloride problem. I de-< ussed vunuu> aspect-,-. with J)r Helmuth A. M. A Montesamj, R. (1975) Mutagenicity of vinyl o I do rule, ehloroethylene oxide, eh loro- Burtseh (International Agency for Rcscuieh on Cancer. Lyon). Profe*-or HiTinmni Bolt (InMitut acctaldehydt4 and chlorocthanul. Piochem. Jiiophys. licit. Common., 63, 393. fiir Phnrmakologic der Unucisitut, Mmnz). Pro OsTEHMAN`fjOLKAH, S., HVLTMAUK, 1).. Sl(il5UI>AeK, fessor ]betrich Hrnsdder (Institnt fur Pharma- 1)., Callkman*, C. J., Gotuk. ]<. & Khiucnjikku, lodogie wtul Toxtkdogie der Cmversituf, Wurzburg), Dr.-s James and Elizabeth Miller (MrArdlo Labora tory for Cancer, Research, University of Wisconsin, Madison) and Dr Rov SdT|iiil (Paterson Laboratory, ('. A. (1977) Alkylation of DXA and proteins in mice exposed to vinyl chloride. Iliochcm. Hiophys. lies. Connnun., 76, 259. PniLues, K, A., Zaiilkh, S. A. & Gauko, A.d. (HKU) Christie Hospital S; Holt Radium Institute, Man* cl ie*ter). (<> whom 1 should like to (Wjuvss my best thanks, Direction of rnutageminduced lesions in isolated DXA using a new ttucillnx mthfilin transformationbasf`d assay. Mutat. lies., 74, 297. REFERENCES Kanni-o, U., Johansson, A., Ramkl, (*. <fc VVaoiitMeistlu. C. A. (1974) The mutagenicity of vinyl Raiuiin, A., Baktncm, H., Lkcontk. 1*. & Kaiimax, chloride after metabolic activation. .4 mbto, 3, 194. M, (1981) Studios on the miscoding properties of ScBxt.LEK, s. & Sinokk, J3. (1981) Transcriptionai 1 ..Y^-othenoadenmc and 3.A'`i-cthenocyt nsine, errors and ambiguity resulting from the presence PNA reaction products of vinyl chloride of l,A'fl-ctheioadeuoMue or H,*Y4-ethenocvtidun' metabolites during in vitro synthesis, Xucleic in polynhonucleotidcw. Xucle.ir Acid# lies., 9, 3(if>. Arid# lies., 9, :j7f). Tocal, Sl.iJ.fc FkKsco, J, K. (1976) Complementary BltUtNAT, .L, ( IV'.SIOI.KA, .7,. CiOKVjrKr, I'.. Adamiak, hu-e puirtng and the origin of substitution R. \Y.. Kitzv/.uMut, W. *}. U'lKWiouGw^Ki, M, mutations. A'u/arr, 263, 285. 41