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1.
Dichloroacetic acid reduces Ha-ras codon 61 mutations in liver tumors from female B6C3F1 mice 总被引:2,自引:0,他引:2
Dichloroacetic acid (DCA), a disinfection by-product of chlorination found
in drinking water, is a hepatocarcinogenic in the B6C3F1 mouse. Previous
studies have shown that DCA does not significantly alter the incidence of
Ha-ras codon 61 mutations in male mouse liver carcinomas from that observed
in spontaneous tumors (approximately 50% have Ha-ras mutations) but it
alters the proportions of mutations that occur in Ha- ras codon 61.
Twenty-two tumors were produced in female B6C3F1 mice after treatment with
3.5 g DCA per liter of drinking water over a period of 104 weeks. To detect
potential Ha-ras mutations in the liver tumor tissue of female B6C3F1 mice,
genomic DNA was isolated from tumors that had been frozen. The polymerase
chain reaction (PCR) and single-stranded conformational polymorphism (SSCP)
was used to screen tumor DNA for mutations in Ha-ras exon 2. In DNA from
liver tumors in female B6C3F1 mice induced by DCA-treatment we found only
one mutation in exon 2 among the 22 tumors analyzed (4.5%).
Direct-sequencing of exon 2 revealed a CAA to CTA transversion in Ha-ras
codon 61. The result of this study indicates that tumor formation in
DCA-treated female B6C3F1 mice is, therefore, not associated with a
mutationally activated Ha-ras codon 61. This result differs from previous
results obtained in male B6C3F1 mice.
相似文献
2.
Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acids 总被引:2,自引:0,他引:2
Dichloroacetic (DCA) and trichloroacetic (TCA) acids, two majorby-products formed during chlorine disinfection of drinkingwater, increase the incidence of tumors in B6C3F1 mice by 6-and 3-fold respectively. In order to understand better the mechanismby which these two compounds induce liver tumors, the incidenceand spectrum of mutations in the K- and H-ras proto-oncogenesin these tumors were analyzed. DNA from spontaneous, DCA- andTCA-induced liver tumors from B6C3F1 male mice was evaluatedfor point mutations in exons 1, 2 and 3 of the two genes bysingle-stranded conformation polymorphism. Results demonstrateda similar incidence of mutations for exon 2 of H-ras in spontaneouscarcinomas (58%), and in carcinomas induced by DCA 3.5 g/l (50%),1.0 g/1(48%) and TCA 4.5 g/l (45%). Only four samples showedmutations in the other exons of H-ras or in K-ras. Sequenceanalysis of spontaneous tumor samples with second exon H-rasmutations revealed a change in codon 61 from CAA to AAA in 80%and CAA to CGA in 20% of tumors. In contrast, tumors with H-rasmutations from DCA-treated mice revealed a H-61 change fromCAA to AAA in 21 % at 3.5 g/l and 16% at 1.0 g/l. CAA to CGAwas observed in 50% of tumors from mice given DCA 3.5 or 1.0g/l, and CAA to CTA was present in 29% and 34% of the two dosagegroups respectively. Interestingly, TCA showed the same mutationalspectrum as the spontaneous liver tumors. The data indicatesthat induction of liver carcinoma by DCA and TCA involves activationof the H-ras proto-oncogene at a frequency similar to that observedin spontaneous tumors. However, the mechanism(s) for inducinghepatocellular carcinoma does not appear to be identical forDCA and TCA. 相似文献
3.
N-Nitrosodibenzylamine (NDBzA) is a contaminant found frequently in rubber
baby bottle nipples and pacifiers. To evaluate more fully the mutagenic
potential and analyse the molecular nature of possible mutations induced in
vivo, we have studied the mutagenicity of NDBzA in vivo using the MutaMouse
system. NDBzA, suspended in olive oil, was administered orally once to male
mice at different doses (0, 30, 100, 425 and 750 mg/kg) and the mice were
killed 30 and 90 days after treatment. As a positive control, and to
compare relative mutagenicity, N-nitrosodimethylamine (NDMA) was also
administered to animals in the same experiment at doses of 0, 2, 6 and 10
mg/kg. Mutant frequencies were increased in both 30 and 90 day liver
samples, but not in bone marrow, after both NDBzA and NDMA treatment.
However, NDBzA was >100 times less mutagenic than NDMA. A total of 81
mutants obtained from liver samples of treated animals (750 mg/kg) were
characterized by DNA sequencing. While spontaneous mutations in transgenic
mice have been characterized previously by a preponderance of G:C-->A:T
transitions, mainly at 5'-CpG-3' dinucleotide sites, the predominant type
of NDBzA- induced mutation in this study was transversion, mainly
G:C-->T:A changes. The molecular characteristics of mutations induced by
NDBzA indicate that they may arise from specific unidentified DNA adducts
and benzylation appears to be the primary mechanism involved in formation
of these DNA adducts.
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4.
5.
Chloroform, dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are mouse liver carcinogens that are chlorine disinfection by-products found in drinking water. The effect of chloroform on DCA and TCA-induced hypomethylation and expression of the c-myc gene and on their promotion of liver and kidney tumors was determined. B6C3F1 mice were administered 0, 400, 800 and 1600 mg/l chloroform in drinking water and 500 mg/kg DCA or TCA-administered daily by gavage. DCA, TCA and to a lesser extent chloroform decreased the methylation and increased the mRNA expression of the c-myc gene. Co-administering chloroform prevented only DCA and not TCA-induced hypomethylation and increased mRNA expression of the gene. The effect of chloroform on tumor promotion by DCA and TCA was determined in female and male B6C3F1 mice initiated on day 15 of age with N-methyl-N-nitrosourea. Starting at 5 weeks of age, the mice received in their drinking water DCA (3.2 g/l) or TCA (4.0 g/l) with 0, 800 or 1600 mg/l chloroform until they were killed at 36 weeks. Liver tumors promoted by DCA and TCA were predominantly basophilic except for DCA-treated female mice that were eosinophilic. Only DCA promoted foci of altered hepatocytes and they were eosinophilic in both sexes. Chloroform prevented DCA, but not TCA promotion of liver foci and tumors. In male mice, TCA promoted kidney tumors while DCA promoted kidney tumors only when co-administered with chloroform. Hence, chloroform prevented the hypomethylation and increased mRNA expression of the c-myc gene and the promotion of liver tumors by DCA, while enhancing DCA-promotion of kidney tumors. Thus, the concurrent exposure to two carcinogens, chloroform and DCA resulted in less than additive activity in one organ and synergism in another organ. 相似文献
6.
1,3-Butadiene (BD) is a genotoxic carcinogen that is bioactivated to at
least two mutagenic metabolites: 1,2-epoxybutene (EB) and 1,2:3,4-
diepoxybutane (DEB). We reported previously that lacI transgenic mice
exposed to BD had an increased frequency of specific base substitution
mutations in the bone marrow and spleen relative to unexposed controls. In
the experiments described here, we determined the mutagenicity and
mutational spectrum of EB in Rat2 lacI transgenic fibroblasts as a means of
assessing the contribution of this metabolite to the lacI mutational
spectrum of BD. Rat2 cells were exposed to 0, 0.4, 0.6, 0.8 or 1.0 mM EB
for 24 h, resulting in a range of cell survival from 100 to 15%,
respectively. Mutagenicity was assessed at 0, 0.6 and 1.0 mM EB. Unexposed
controls had a background mutant frequency of 6 +/- 1 +/- 10(-5), while the
mutant frequency in cells exposed to 0.6 and 1.0 mM EB was increased 2- and
3-fold, respectively. DNA sequence analysis of 154 lacI mutants recovered
in these experiments revealed an increase in the frequency of specific base
substitution mutations in cells exposed to 1.0 mM EB compared with
controls. These included G:C-->A:T transitions at non-CpG sites,
G:C-->T:A transversions and A:T-->T:A transversions, which have all
been observed in lacI mutants isolated from transgenic mice exposed to BD.
These results suggest that EB causes mutation primarily by base
substitution and that the spectrum of these mutations closely resembles
that of BD. These data, along with previous findings from our laboratory,
suggest that EB is more likely than DEB to be primarily responsible for the
lacI mutational spectrum observed in lacI transgenic mice exposed to BD.
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7.
Hong HL; Devereux TR; Melnick RL; Eldridge SR; Greenwell A; Haseman J; Boorman GA; Sills RC 《Carcinogenesis》1997,18(4):783-789
Isoprene is the 2-methyl analog of 1,3-butadiene, a genotoxic and
carcinogenic compound in rats and mice. Male B6C3F1 mice were exposed to 0,
2200 or 7000 ppm isoprene by inhalation (6 h/day; 5 days/week) for 26
weeks. Following a 26-week recovery period, an increased incidence of
Harderian gland (HG) neoplasms was observed at both concentrations. The
present study was designed to characterize genetic alterations in the K-ras
and H-ras protooncogenes in HG neoplasms. Mutations in K-ras and H-ras were
identified by single-strand conformational analysis and direct sequencing
of polymerase chain reaction (PCR) amplified DNA, isolated from
paraffin-embedded sections of HG neoplasms. A higher frequency of ras
mutations, in particular K- ras mutations, was detected in isoprene-induced
neoplasms than in 1,3- butadiene-induced or control HG neoplasms. All of
the isoprene-induced HG neoplasms exhibited activated K-ras (60%) or H-ras
(40%) mutations. In contrast, ras mutations were detected in 69% of HG
neoplasms from 1,3-butadiene exposed mice (14% K-ras and 55% H-ras) and in
56% of HG neoplasms obtained from control B6C3F1 mice (8% K-ras and 48%
H-ras). The predominant mutations in isoprene-induced HG neoplasms, but not
in previously or newly analysed 1,3-butadiene-induced HG neoplasms,
consisted of A-->T transversions (CAA-->CTA) at K-ras codon 61
(15/30) and C-->A transversions (CAA-->AAA) at H-ras codon 61 (8/30).
Two- thirds of the K-ras CTA mutations were detected in HG neoplasms from
the 2200 ppm exposure group while one-third was present in the 7000 ppm
group. Isoprene-induced HG neoplasms with K-ras or H-ras mutations had an
elevated proliferating cell nuclear antigen (PCNA) index, compared to
spontaneous HG neoplasms without ras mutations. The high frequency and
specificity of the ras mutation profile suggest that ras protooncogene
activation contributes to isoprene-induced HG tumorigenesis.
相似文献
8.
Pletsa V; Valavanis C; van Delft JH; Steenwinkel MJ; Kyrtopoulos SA 《Carcinogenesis》1997,18(11):2191-2196
The DNA damaging and mutagenic activities of procarbazine, a methylating
drug employed in cancer chemotherapy and suspected of causing
therapy-related leukaemia, were investigated in the liver and bone marrow
of lambda lacZ transgenic mice (MutaMouse). The drug was administered using
two different protocols, a 'high-dose' one involving 5 daily doses of 200
mg/kg, expected to cause depletion of the repair enzyme O6-alkylguanine-DNA
alkyltransferase (AGT) and thus favour the selective accumulation of the
premutagenic lesion O6-methylguanine (O6- meG) relative to other adducts,
and a 'low-dose' one involving 10 daily doses of 20 mg/kg procarbazine.
Substantial accumulation of O6-meG was observed in both tissues examined 6
h after the end of the 'high-dose' treatment, with the liver accumulating
somewhat higher levels than the bone marrow (28.0 +/- 1.8 fmol/microg DNA
and 18.5 +/- 1.1 fmol/microg DNA respectively). However, significant
increases in mutant frequency 10 days after the end of treatment were
observed only in the bone marrow, reaching a 16-fold increase over
background following the 5 x 200 mg/kg treatment. Sequence analysis of the
mutations induced after this treatment revealed a mixed spectrum, in which
G:C-->A:T transitions (characteristic of O6-meG miscoding) were only a
secondary feature: Among 20 mutants analysed, only six such mutations were
found, including three at CpG sites, which might have arisen from
deamination of 5-methylcytosine. The other mutations observed included 1
A:T-->G:C transition, five transversions (one G:C-->T:A, one double
G:C-->C:G, two A:T-->T:A, one A:T-->C:G), five deletions and three
insertions. The mechanistic and clinical significance of these findings is
discussed.
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9.
A spectrum of mutations induced by crotonaldehyde in shuttle vector plasmids propagated in human cells 总被引:2,自引:0,他引:2
A spectrum of crotonaldehyde-induced mutations in the supF gene of the
shuttle vector plasmid pMY189 replicated in human fibroblast cells was
examined. Base sequence analysis of 104 plasmids with mutations in the supF
gene revealed that the majority of the mutations were base substitutions
(85%) and the rest were frameshifts (15%). A single base substitution was
most frequently found (47%), while 25% had multiple base substitutions and
interestingly 13% had tandem (adjacent two) base substitutions. Of the base
substitution mutations, 50% were G:C-->T:A transversions and 23% were
G:C-->A:T transitions. The mutations were not distributed randomly but
were located at several hotspots, most of which were G:C base pairs in
5'-AAGG-3' (or 5'-CCTT-3') sequences. Production of propanodeoxyguanosine
adducts may be related to such specificity in the mutation spectrum.
相似文献
10.
Liu Q; Wang Y; Crist KA; Wang ZY; Lou YR; Huang MT; Conney AH; You M 《Carcinogenesis》1998,19(7):1257-1262
In the present study, administration of green tea to SKH-1 mice, via the
drinking fluid, was found to significantly reduce the incidence and volume
of ultraviolet B (UVB) radiation-induced skin tumors. Thirty-six skin
tumors induced by UVB and 32 skin tumors induced by UVB, in mice treated
with green tea in their drinking water, were collected and examined for the
presence of mutations in the p53 gene. Polymerase chain reaction products
from p53 exons 5-8 were screened by single- strand conformation
polymorphism and direct sequence analyses. Eight of 36 UVB-induced tumors
contained nine p53 mutations, with four in exon 5 and five in exon 8. In
contrast, nine of 32 UVB-induced tumors in mice treated with green tea
contained 11 p53 mutations, with two in exon 5, five in exon 6 and four in
exon 8. All of the p53 mutations occurred at dipyrimidine sequences. These
results were further corroborated by p53 immunohistochemistry. The most
frequent mutations were C-->T or T-->C transitions, which are
consistent with the genetic alterations caused by UVB exposure.
Interestingly, mutations found in exon 6 of the p53 gene occurred only in
tumors from the UVB/green tea group. Thus, the tumors observed in
UVB/green-tea-treated mice have a different exon distribution of p53
mutations than tumors obtained from mice treated with UVB alone.
相似文献
11.
Bromodichloromethane (BDCM) and bromoform (TBM) have been demonstrated to be colon carcinogens in male and female F344/N rats following administration by corn oil gavage. Our chronic bioassay of BDCM administered in the drinking water failed to demonstrate colon cancer in male F344/N rats. In the present study we addressed the capability of trihalomethanes (THMs) administered in drinking water to induce aberrant crypt foci (ACF), early putative preneoplastic lesions, in the colons of male F344/N rats and B6C3F(1) mice. BDCM was tested in the A/J mouse strain. Rats and B6C3F(1) mice were exposed to isomolar concentrations of the THMs [0.5 g/l chloroform (TCM), 0.7 g/l BDCM, 0.9 g/l dibromochloromethane (DBCM), or 1.1 g/l (TBM)] for 13 weeks. A/J mice were exposed to 0.5 g/l BDCM in the drinking water for 13 and 30 weeks. Deionized water and 0.25% Alkamuls EL-620 were the negative and vehicle controls. ACF incidence (percent) and number (ACF/colon) for the rat were: combined controls, 0; AOM, 100%, 27.17+/-6.28 (P<0.01); TCM, 16.7%, 0.17+/-0.17; BDCM, 83.3%, 1.50+/-0.56 (P<0.01); DBCM, 50%, 1.17+/-0.65 (P<0.01); TBM, 66.7%, 1.17+/-0.40 (P<0.01). THM-induced ACF primarily occurred in the rectal segment of the colon (92%). No ACF were observed in the colons of B6C3F(1) mice following 13 weeks of THM treatment or in the colons of A/J mice following 13 and 30 weeks of BDCM exposure. These studies demonstrate that brominated THMs administered in the drinking water significantly induced preneoplastic ACF in the colon of rats. 相似文献
12.
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), a strong mutagen/carcinogen,
belongs to a group of heterocyclic amines that are formed (ng/g amounts)
during the cooking of protein containing food. The mutational specificity
of IQ in Escherichia coli was determined in a forward mutation assay using
the yeast URA3 gene as a target. The plasmid pTU-AC, containing the target
URA3, was randomly modified in vitro using N-hydroxy-IQ, and subsequently
transformed into an E. coli pyrF strain (DB6656). Mutant clones were
directly selected by their ability to grow on medium containing
5-fluoro-orotic acid which is toxic to URA3+ clones and thereby selects for
URA3- mutants. Single Strand Conformation Polymorphism (SSCP) was used to
map the mutation- containing regions of URA3, so that it was necessary to
sequence only the relevant, mutation-containing fragment and not the entire
gene. At a modification level of 7 IQ-lesions/URA3 gene, the predominant
mutations were base substitutions (approximately 70%), followed by complex
gene rearrangements (approximately 20%) and frameshifts (approximately
10%). More than 96% of the base substitutions occurred at G:C base pairs
and were predominantly G:C-->A:T transitions, followed by G:C-->T:A
and G:C-->C:G transversions. Next neighbour analysis revealed that
deoxyguanosines situated within the sequence 5'- TGC were more susceptible
to mutations induced by IQ. With one exception, all frameshift mutations
were -1 deletions at runs of three consecutive dGs. At higher
IQ-modification levels, predominantly complex sequence rearrangements were
observed.
相似文献
13.
Molecular analysis of lacI mutants from bone marrow of B6C3F1 transgenic mice following inhalation exposure to 1,3-butadiene 总被引:1,自引:1,他引:1
Chronic exposure to 1,3-butadiene (BD) results in early occurrenceand high incidence of lethal lymphomas in male B6C3F1 mice.Male B6C3F1 lacI transgenic mice (BigBlueTM) were exposed byinhalation to 0, 62.5, 625 or 1250 p.p.m. BD for 4 weeks (6h/day, 5 days/week). The lacI- mutant frequency and mutationalspectrum were evaluated in DNA isolated from bone marrow cells.Two weeks after exposure the lacI- mutant frequency in bonemarrow from BD-exposed mice had increased 2- to 3.5-fold overair control mice. DNA sequence analysis of 56 and 54 lacI- mutantsfrom the air control and butadiene-exposed groups, respectively,demonstrated that there was a shift in the spectrum of basesubstitution mutations at A:T sites in BD-exposed mice (6/26)compared to the air control mice (2/45). A:T 相似文献
14.
Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated the hepatocarcinogenicity of DCA in mice when administered in drinking water. The mechanism of DCA carcinogenicity is not clear and we speculate that changes in gene expression may be important. In order to analyze early changes in gene expression induced by DCA treatment we used the differential display method. Mice were treated with 2 g/l DCA in drinking water for 4 weeks. Total RNAs were obtained from livers of both control and treated mice for analysis. Of approximately 48 000 bands on the differential display gels representing an estimated 96% of RNA species, 381 showed differences in intensity. After cloning and confirmation by both reverse-northern and northern analyses, six differentially expressed genes were found. The expression of five of these genes was suppressed in the DCA-treated mice while one was induced. After sequencing, four genes were identified and two were matched to expressed sequence tags through the BLAST program. These genes are alpha-1 protease inhibitor, cytochrome b5, stearoyl-CoA desaturase and carboxylesterase. Stearoyl-CoA desaturase was induced approximately 3-fold in the livers of DCA-treated mice and the other three genes were suppressed approximately 3-fold. Stearoyl-CoA desaturase, cytochrome b5 and carboxylesterase are endoplasmic reticulum membrane-bound enzymes involved in fatty acid metabolism. The expression pattern of four of these genes was similar in DCA-induced hepatocellular carcinomas and the 4 week DCA-treated mouse livers. The expression of stearoyl-CoA desaturase and one of the unidentified genes returned to control levels in the carcinomas. Understanding the roles and interactions between these genes may shed light on the mechanism of DCA carcinogenesis. 相似文献
15.
Strain differences in hepatic tumor promotion by phenobarbital in diethylnitrosamine- and dimethylnitrosamine-initiated infant male mice 总被引:2,自引:0,他引:2
The effects of phenobarbital (PB) on hepatocellular carcinogenesisin three strains of nitrosamine-initiated infant male mice wereevaluated. Fifteen-day-old C57Bl/6NCr1BR (C57Bl), C3H/HeNCr1BR(C3H) and B6C3F1 mice were treated with a single i.p. injectionof either diethylnitrosamine (DENA) (5 µg/body wt), dimethylnitrosamine(DMNA) (5 µg/body wt) or saline. One-half of the treatedmice received PB via the drinking water (500 mg/l) for 24 weeks.The remaining treated mice were given deionized drinking water.Mice were killed at 28 weeks of age and hepatic lesions wereevaluated. Only animals that received DENA or DMNA exhibitedtumors. C3H mice treated with DENA + PB demonstrated a significantincrease in hepatic adenoma number compared to C3H mice exposedto DENA only. Conversely, B6C3F1 males treated with DENA + PBexhibited a significant decrease in the number of hepatic adenomascompared to B6C3F1 males treated with DENA alone. No changewas noted in adenoma size in B6C3F1 mice treated with DENA +PB from those receiving DENA only. Chronic PB exposure of C57B1males previously treated with DENA had no effect on hepaticadenoma number or size. C3H mice treated with DMNA + PB displayedan increase in both adenoma size and adenoma number comparedto C3H mice receiving DMNA only. Similarly, in B6C3F1 mice,PB treatment increased both the adenoma incidence and adenomanumber in DMNA initiated mice. PB had no effect on hepatic adenomaincidence or number in DMNA-treated C57B1 mice. These data suggestthat the ability of PB to promote hepatic tumorigenesis in the15-day-old initiated mouse is dependent on both the strain ofthe mouse and the initiating chemical carcinogen. 相似文献
16.
Male F-344 rats were fed for 15 weeks a methyl-deficient L-amino acid defined diet containing 0.05% DL-ethionine. Nodules protruding from the surface of the liver were dissected free of surrounding tissue, and polyadenylated RNA isolated from the nodules was reverse transcribed. The region of the p53 gene comprising codons 120-290 was amplified by the polymerase chain reaction, and cDNAs were sequenced. Mutations were detected in nodules obtained from 7 of 12 rats. In all seven cases, the same two point mutations were present. The first was at the first base of codon 246 and consisted of a C-->T transition (C:G-->T:A, Arg-->Cys), while the second was at the second base of codon 247 and consisted of a G-->T transversion (G:C-->T:A, Arg-->Leu). It is concluded that the hepatocarcinogen ethionine induces specific hot-spot p53 gene mutations; this is in contrast to the mutations at various sites previously observed to occur in rats fed a hepatocarcinogenic methyl-deficient diet alone. The results also provide the first evidence that ethionine is mutagenic in the rat. 相似文献
17.
Irradiation of SKH-1 mice with UVB light for 20 weeks resulted in a large number of patches of epidermal cells, which was visualized with an antibody that recognizes mutated p53 protein. Oral treatment of mice with caffeine (0.4 mg/ml) or green tea (6 mg tea solids/ml) as the drinking fluid during UVB irradiation decreased the number of patches by approximately 40%. Sequencing analysis of the p53 gene (exons 3 to 9) detected 88, 82 or 39 point mutations in 67, 70 or 29 patches from water, caffeine or tea treated mice, respectively. A major hotspot at codon 270 (Arg-->Cys) accounted for 47.7% (water), 70.7% (caffeine) or 46.2% (tea) of all mutations. Patches from caffeine treated mice had fewer types of mutations than patches from mice treated with water or tea. Administration of caffeine or tea during 20 weeks of UVB irradiation eliminated mutations at codons 149 (Pro-->Ser) and 210 (Arg-->Cys) but increased the frequency of mutations at codon 238 (Ser-->Phe). Topical applications of caffeine (1.2 mg in 100 microl acetone) once a day, five times a week for 6 weeks after stopping UVB decreased the number of patches by 63% when compared with mice treated with acetone. DNA sequencing analysis detected 63 and 68 mutations in 48 and 57 patches from acetone or caffeine treated mice, respectively. Although no differences in the frequency, position or types of mutations were observed, the caffeine group harbored less homozygous mutations (12.3% of the total) than the acetone group (31.3% of the total, P = 0.029). In summary, oral treatment of mice with caffeine or green tea during chronic UVB irradiation changed the mutation profile of the p53 gene in early mutant p53 positive epidermal patches, and topical applications of caffeine after discontinuation of chronic UVB irradiation specifically eliminated patches harboring homozygous p53 mutations. 相似文献
18.
O6-Methylguanine (O6MeG) and O4-methylthymine (O4MeT) are potentially
mutagenic DNA lesions that cause G:C-->A:T and A:T-->G:C transition
mutations by mispairing during DNA replication, and the repair of O6MeG and
O4MeT by DNA repair methyltransferases (MTases) is therefore expected to
prevent methylation-induced transitions. The efficiency of O6MeG and O4MeT
repair by different MTases can vary by several hundred- fold and the aim of
this study was to establish the biological consequences of such differences
in the efficiency of repair. The ability of three microbial and two
mammalian MTases to prevent methylation-induced G:C-->A:T and
A:T-->G:C transitions is taken as a measure of their ability to repair
O6MeG and O4MeT in vivo respectively. All five MTases give complete
protection against G:C-- >A:T transitions. However, while the microbial
MTases give complete protection against A:T-->G:C transitions, the
mammalian MTases actually sensitize cells to A:T-->G:C transitions. We
hypothesize that the mammalian MTases bind O4MeT lesions in vivo but that,
because they are extremely slow at subsequent methyl transfer, binding
shields O4MeT from repair by the nucleotide excision repair pathway.
Results are presented to support this hypothesis.
相似文献
19.
Hernandez LG Forkert PG 《International journal of cancer. Journal international du cancer》2007,120(7):1426-1433
Vinyl carbamate (VC) is a metabolite of ethyl carbamate (EC), a chemical found in alcoholic beverages and fermented foods. We undertook this study to: (i) evaluate the ability of both EC and VC to induce gene mutations in lung and various extrapulmonary tissues, and (ii) identify the type of mutations induced by the two compounds in various tissues. F1 (Big Blue x A/J) transgenic mice harboring the lambda cII transgene were used for identification and quantitation of mutations in vivo. Time-course studies in lung showed a plateau in mutant frequency (MF) 4 weeks after VC treatment, at which time mutations were fixed and were about 4-fold higher than in controls. Dose-dependent increases in MF were detected in the lung and small intestine (SI) after treatment with 15-75 mg/kg, i.p., of VC. VC was mutagenic in the lung and SI at doses of 45, 60 and 75 mg/kg. Sequencing of the cII gene in lung and SI showed that VC induced mainly A:T-->G:C transitions and A:T-->T:A transversions. EC was also mutagenic in the lung at 500 and 1,000 mg/kg and elicited mainly G:C-->A:T transitions. A VC dose of 60 mg/kg elicited a similar level of MF as an EC dose of 1,000 mg/kg. At 4 weeks after treatment, neither VC nor EC elicited mutations in the colon, bone marrow or kidney. These results demonstrated that VC and EC are mutagenic in vivo and affirm that VC is a more potent mutagen than EC. 相似文献
20.
Although oxazepam (Serax), a widely used benzodiazepine anxiolytic, does not induce gene mutations in vitro or chromosomal aberrations in vivo, it was found to be a hepatocarcinogen in a 2 year bioassay in B6C3F1 mice. Thus, it was of interest to determine whether this carcinogen is mutagenic in vivo. Male B6C3F1 Big Blue transgenic mice were fed 2500 p.p.m. oxazepam or control diet alone for 180 days and killed on the next day. The mutant frequency (MF) of lacI in control mice was 5.02 +/- 2.4x10(5), whereas the MF in the oxazepam-treated mice was 9.17 +/- 4.82x10(-5), a significant increase (P < 0.05). Correction of the mutant frequency of lacI from the oxazepam-treated mice for clonality resulted in a decrease in the mean mutant frequency to 8.15 +/- 2. 54x10(-5). Although the mutant frequency difference was small, sequencing of a random collection of the mutants from each oxazepam-exposed mouse showed a significant difference (P < 0.015) in the mutation spectrum compared with that from control mice. In the oxazepam-exposed mice, an increase in G:C-->T:A and G:C-->C:G transversions and a concomitant decrease in G:C-->A:T transitions were observed. Clonal expansion of mutations at guanines in 5'-CpG-3' sequencing contexts at three sites was noted. It is postulated that some of the mutations found in the oxazepam-derived spectrum were due to oxidative damage elicited by induction of CYP2B isozymes as the result of chronic oxazepam administration. This study demonstrates that the in vivo Big Blue transgenic rodent mutation assay can detect mutations derived from a carcinogen that did not induce gene mutations in vitro or micronuclei in mouse bone marrow. Moreover, the sequencing of the recovered mutants can distinguish between the mutation spectrum from treated mice compared with that from control mice, thereby confirming the genotoxic consequences. 相似文献