DNA alkylation by vinyl chloride metabolites: Etheno derivatives or 7-alkylation of guanine?

Laib, R. J.; Gwinner, L.M.; Bolt, Hermann M.

doi:10.1016/0009-2797(81)90179-4

Cited by 76 publications

(33 citation statements)

References 21 publications

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“…On the other hand, the occurrence of all ofthe HO-DHE-induced mutations at an A-T base pair is surprising, since >90% of the DNA adducts in mouse liver DNA in vivo after a carcinogenic dose are at the N2 position of deoxyguanosine residues (12). Although the data on adduct formation from VC in DNA are less complete (32), the data for a closely related carcinogen, vinyl choride (33), indicate that the covalent binding occurs primarily at the N7 position of deoxyguanosine residues. In contrast, the mutation spectrum (AT -* TA) observed in 6 of 7 VC-induced hepatomas is consistent with their resulting from miscoding deoxyadenosine adducts (34,35).…”

Section: Discussionmentioning

confidence: 99%

Activating mutations of the c-Ha-ras protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse.

Wiseman¹,

Stowers²,

Miller³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

224

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Activated c-Ha-ras protooncogenes have recently been identified in the DNA of some spontaneous hepatic tumors found in 2-year-old B6C3 F1 mice. Activation of c-Ha-ras has now been demonstrated in DNA from well-differentiated hepatomas initiated by a single dose of carcinogen given to male B6C3 F1 mice at 12 days of age. DNA from each of 25 hepatomas, induced by N-hydroxy-2-acetylaminofluorene, vinyl carbamate, or l'-hydroxy-2',3'-dehydroestragole, contained transforming activity in the NIH 3T3 transfection assay. Southern analysis of NIH 3T3 cells transformed by DNA from 24 of these hepatomas revealed amplified and/or rearranged restriction fragments homologous to a Ha-ras probe. The other tumor contained an activated Ki-ras gene. Immunoprecipitation and NaDodSO4/PAGE analysis of p21 ras proteins in NIH 3T3 transformants derived from a majority of the hepatomas suggested that the activating mutations were localized in the 61st codon of the c-Ha-ras gene. Creation of a new Xba I restriction site by an AT --TA transversion at the second position of codon 61 was detected in DNA from primary tumors and NIH 3T3 cells transformed by DNA from 6 of 7 vinyl carbamate-and 5 of 10 1'-hydroxy-2',3'-dehydroestragole-induced hepatomas. Selective oligonucleotide hybridization demonstrated a CG -+ AT transversion at the first position of the 61st codon in NIH 3T3 transformants derived from 7 of 7 N-hydroxy-2-acetylaminofluorene-induced hepatomas. By the same criterion, an AT --GC transition at the second position of codon 61 was the activating mutation in 1 of 7 vinyl carbamate-and 5 of 10 1'-hydroxy-2',3'-dehydroestragole-induced tumors. Thus, c-Ha-ras activation is apparently an early event in B6C3 F1 mouse hepatocarcinogenesis that results directly from reaction of ultimate chemical carcinogens with this gene in vivo. protooncogenes, particularly members of the ras family, have been detected in a variety ofhuman malignancies (2) and in a high percentage of several kinds of rodent tumors (4-6). Point mutations in the 12th, 13th, or 61st codons of ras protooncogenes appear to be responsible for activation in vivo (2, 7).Recent studies demonstrated that DNA from some hepatic tumors that developed spontaneously in 2-year-old B6C3 F1 mice contained transforming activity in the NIH 3T3 transfection assay (8, 9). Activated alleles of the c-Ha-ras gene were associated with this transforming activity in 11 of 13 tumors, while non-ras genes were activated in the other two cases (9). Administration of single doses of a wide variety of chemical carcinogens to 12-day-old male B6C3 F1 mice results in the formation of multiple hepatomas by 7-9 months in the absence of any further treatments (10-12). We have now characterized the activated c-Ha-ras genes in hepatomas induced in these mice by three structurally diverse chemical carcinogens. The selection of these three chemicals was based on the reactions of their electrophilic metabolites at different sites on DNA (10-12). The distinct patterns of c-Ha-ras mutations observed for eac...

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Section: Discussionmentioning

confidence: 99%

Activating mutations of the c-Ha-ras protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse.

Wiseman¹,

Stowers²,

Miller³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

224

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“…Vinyl chloride is metabolized by the monooxygenase P450 system into chloroethylene oxide (3), a very unstable alkylating agent (4). The stable metabolite, chloroacetaldehyde, is formed by chemical rearrangement (5) and, as a bifunctional agent, generates 1,N6-ethenoadenine, 3,N4-ethenocytosine, N2,3-ethenoguanine (eG), and 1,N2-ethenoguanine (refs. 6-8; re-viewed in ref.…”

mentioning

confidence: 99%

The vinyl chloride DNA derivative N2,3-ethenoguanine produces G----A transitions in Escherichia coli.

Cheng

Preston

Cahill

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

128

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Vinyl chloride is a known human and rodent carcinogen that forms several cyclic base derivatives in DNA. The mutagenic potential ofthese derivatives has been examined in vitro but not in vivo. One of these derivatives, N2,3-ethenoguanine (eG), is known to base pair with both cytosine and thymine during in vitro DNA synthesis, which would result in G -* A transitions. To determine the base pairing specificity of this labile guanine derivative in Escherichia coi, we have developed a genetic reversion assay for guanine derivatives. The assay utilizes DNA polymerase-mediated analogue insertion into a bacteriophage vector, M13G*1, which detects all single-base substitutions at position 141 of the lacZa gene by change in plaque color. After the insertion of a single vG opposite the template cytosine at position 141 by use of edGTP and DNA polymerase and further extension with all four normal dNTPs, the DNA was transfected into E. coil. Transfection of M13G*1 containing EG at the target site yielded 135 mutants among 26,500 plaques, 134 of which represented G -* A transitions. The uncorrected mutation frequency was 0.5%, as compared with the control value, :0.02%; when corrected for eG content and penetrance, the calculated mutagenic potential of eG (mutations/analogue) was about 13%. We thus conclude that eG specifically induces G -* A transitions during DNA replication in E. colU. The M13G*1 assay may permit the testing of other labile guanine derivatives not otherwise amenable to mutagenesis studies.

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“…Since 7-(2-oxoethyl)guanine is also formed by vinyJ chloride (Laib et al, 1981), Svensson (1988) postulated a common ultimate carcinogen for the two compounds and compared their potency to form DNA-adducts with their respective carcinogenic potencies. This quantitative comparison revealed a good correlation of the ethyl carbamate data with the vinyl chloride data.…”

Section: Dna-adduct Formationmentioning

confidence: 99%

The carcinogenic potential of ethyl carbamate (urethane): Risk assessment at human dietary exposure levels

Schlatter

Lutz

1990

Food and Chemical Toxicology

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Summary-Ethyl carbamate is found in fermented foods: bread contains 3-15 ng/g, stone-fruit brandies 200-20,000 ngfg, and about one-third of table-wine samples analysed contained more than 10 ng/g. In animals, ethyl carbamate is degraded to C0 2 , H 2 0 and NH 3 , with intermediate formation ofethanol. This degradation has been shown tobe inhibited (postponed) in the mouse by ethanol concentrations in the blood of about 0.15% and higher. A quantitatively minor pathway involves a two-step oxidation of the ethyl group to vinyl carbamate and epoxyethyl carbamate, the postulated electrophilic moiety that reacts with DNA. This reaction is probably the mode of the mutagenic action observed in many cellular and animal systems. The fact that only vinyl carbamate, but not ethyl carbamate, is mutagenic in a standard Ames test is probably because there is insufficient production of the intermediate oxidation product in the standard test. Consistent with this metabolism is the carcinogenic activity of ethyl carbamate in various animal species and in different organs; this activity can be seen even after a single high dose in early life. Quantitative analysis of the total tumour incidences after chronic exposure of rats and mice to 0.1-12.5 mg ethyl carbamate/kg body weightjday in the drinking-water showed a dose-related increase. The main target organs were the mammary gland (female rats and mice having similar susceptibilities) and the Jung (mice only). On the basis of sex-and organ-specific tumour data and with a linear extrapolation to a negligible increase of the lifetime tumour incidence by 0.0001% ( one additional tumour in one milüon individuals exposed for life), a "virtually safe dose .. of 20 to 80 ng/kg body weight/day was estimated. The daily burden reached under normal dietary habits without alcoholic beverages is in the range of about 20 ng/kg body weightfday. Regular table-wine consumption would increase the risk by a factor of up to five. Regular drinking of 20 to 40 ml stone-fruit brandy per day could raise the calculated lifetime tumour risk to near 0.01%.

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DNA alkylation by vinyl chloride metabolites: Etheno derivatives or 7-alkylation of guanine?

Cited by 76 publications

References 21 publications

Activating mutations of the c-Ha-ras protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse.

Activating mutations of the c-Ha-ras protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse.

The vinyl chloride DNA derivative N2,3-ethenoguanine produces G----A transitions in Escherichia coli.

The carcinogenic potential of ethyl carbamate (urethane): Risk assessment at human dietary exposure levels

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