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Biomedical subjects

B Bailleul

Publications and source records attributed to B Bailleul.

At least 37 records · Page 2Linked to original sources
PubMed1990

Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter.

The promoter region of the suprabasal keratin 10 gene has been used to direct expression of a mutant human Harvey-ras oncogene to the differentiating cells of the mouse epidermis. Transgenic animals develop hyperkeratosis of the skin and forestomach--the two sites known to express high levels of the keratin 10 polypeptide in vivo. Papillomas subsequently develop on the skin surface, initially at sites subject to biting or scratching such as the base of the tail or behind the ears. The results suggest that the "second event" involved in tumor development in these transgenic animals is the local induction of a mild wounding stimulus. Furthermore, because the H-ras transgene is expressed in suprabasal cells, it appears that cells which have left the stem cell compartment can be induced to form at least benign tumors in vivo.

Animals↗
PubMed1989

Mutagenicity of N2 guanylarylation is SOS functions dependent and reminiscent of the high mutagenic property of 4NQO.

A comparison of the mutagenic potency of the N2 and the C8 guanylarylation of DNA by 4-nitroquinoline 1-oxide (4NQO) was established. The induced mutagenicity by the N2 guanine adduct is dependent on the SOS functions in the host and requires the umuC gene product. This lesion is repaired by the excision repair system and efficiently blocks the replication machinery. The data obtained with the C8 adduct show that this lesion is weakly toxic in the wild-type strain Escherichia coli probably because the efficiency of the replication is affected. This adduct is three times less mutagenic than the N2 adduct. These results suggest that in vivo the high mutagenicity of 4NQO can mainly be ascribed to the N2 guanine adduct.

4-Nitroquinoline-1-oxide↗
PubMed1989

In vitro DNA modification by the ultimate carcinogen of 4-nitroquinoline-1-oxide: influence of superhelicity.

The effect of DNA tertiary structure on in vitro modification by 4-acetoxy-aminoquinoline-1-oxide (Ac-4-HAQO) was investigated. The reactivity of pAT153 plasmid DNA depended on the conformational state of the molecule: it progressively decreased according to the decrease of the superhelical tension, being negatively supercoiled DNA about two times more susceptible than singly-nicked relaxed DNA. HPLC of the three main Ac-4-HAQO adducts showed that 3-(deoxyguanosin-N2-yl)-4-aminoquinoline-1-oxide, N-(deoxyguanosin-C8-yl)-4-aminoquinoline-1-oxide and 3-(deoxyadenosin-N6-yl)-4-aminoquinoline-1-oxide accounted for 50, 25 and 10% of total quinoline DNA base adducts in all DNA conformations tested, except in the negatively supercoiled topoisomers where they accounted for 80, 15 and 5% respectively. DNA modification by Ac-4-HAQO resulted also in the formation of apurinic/apyrimidinic sites and in strand scissions. The quantification of these damages revealed that they represent an important fraction of all damaging events and that their yield is also influenced by DNA superstructure. Thus, these lesions must be considered as important DNA damage induced by Ac-4-HAQO.

4-Nitroquinoline-1-oxide↗
PubMed1989

Chemical induction of oncogene mutations and growth factor activity in mouse skin carcinogenesis.

The goal of understanding the molecular basis of human tumor development has been greatly facilitated by the use of animal model systems in which the etiology of tumor development can be carefully controlled. Environmental chemicals, either naturally occurring or artificially produced, are thought to make a major contribution to the human tumor burden. Many of the concepts of multistage carcinogenesis have been developed and refined using the mouse skin model system and the work described in this article has been carried out in an attempt to analyze the molecular changes that are associated with the initiation of tumor development, the selection of initiated cells to form papillomas, or the progression of premalignant tumors to carcinoma. We have analyzed a number of skin tumors induced in mice by a two-stage initiation and promotion protocol and have detected a high frequency of c-ras oncogene mutations in this system. The mutation found in each case correlates well with the known reactivity of the carcinogens used. It has also been shown that where ras activation occurs this represents an early event in the tumor model system. Transforming growth factor beta is induced in mouse skin by tumor promoter treatment and may therefore play a role in the selection of initiated cells to form papillomas. Additional events, some of which involve the loss of normal ras alleles and possibly tumor suppressor genes, appear to take place at a later stage of carcinogenesis.

Animals↗
PubMed1988

Isolation and characterization of the 5' flanking region of the mouse c-Harvey-ras gene.

The complete 5' flanking region of the murine c-Ha-ras gene was cloned and sequenced. An untranslated exon (-1) was identified and the promoter region of the gene located. Like the rat and human homologues, the murine promoter is GC rich and contains several GC boxes together with a CAAT element, but lacks a TATA box, an arrangement similar to that found in many housekeeping genes. From primer extension studies, the gene was shown to have three transcriptional start sites, whose positions differ from those previously found for the human gene. No alterations in these start sites were detected between the normal gene and activated Ha-ras genes from mouse skin tumors. A region of strong homology between mouse, rat, and human Ha-ras genes exists within the large intron separating exon (-1) from the first coding exon. In addition, from chloramphenicol acetyltransferase assays, the upstream region has promoter activity which appears to be enhanced by the inclusion of sequences within this intron.

Animals↗
PubMed1986

N2-guanyl and N6-adenyl arylation of chicken erythrocyte DNA by the ultimate carcinogen of 4-nitroquinoline 1-oxide.

Great quantities of chicken erythrocyte DNA with high levels of modification were obtained in vitro by reaction with 4-acetoxyaminoquinoline 1-oxide, a model ultimate carcinogen of 4-nitroquinoline 1-oxide. After enzymatic hydrolysis of the modified DNA, the three main adducts were separated and isolated by semipreparative high performance liquid chromatography. These three adducts were already characterized in vivo and in vitro in our previous work (S. Galiègue-Zouitina et al., Cancer Res., 45: 520-525, 1985). The structure of one of them was previously identified as N-(deoxyguanosin-8-yl)-4-aminoquinoline 1-oxide (B. Bailleul et al., Cancer Res., 41: 4559-4565, 1981). In this paper we have identified by mass spectroscopy and nuclear magnetic resonance the structures of the two other main adducts as 3-(deoxyguanosin-N2-yl)-4-aminoquinoline 1-oxide and 3-(deoxyadenosin-N6-yl)-4-aminoquinoline 1-oxide, respectively.

4-Nitroquinoline-1-oxide↗
PubMed1985

Adducts from in vivo action of the carcinogen 4-hydroxyaminoquinoline 1-oxide in rats and from in vitro reaction of 4-acetoxyaminoquinoline 1-oxide with DNA and polynucleotides.

In vivo 4-hydroxyamino[2-3H]quinoline 1-oxide-modified DNA and in vitro 4-acetoxyamino[2-3H]quinoline 1-oxide-modified DNA were enzymatically hydrolyzed, and the hydrolysates were analyzed by high-performance liquid chromatography. The two patterns were compared, and we showed that all of the high-performance liquid chromatography peaks which were recovered from in vivo-modified DNA were present in the hydrolysate of in vitro-modified DNA. Therefore, we used the in vitro 4-acetoxyamino[2-3H]quinoline 1-oxide-modified DNA to investigate the quinoline-purine adducts which are characteristics of the mode of action of the carcinogen 4-nitroquinoline 1-oxide. By comparison with the enzymatic hydrolysates of 4-acetoxyamino[2-3H]quinoline 1-oxide-modified covalent poly(deoxyadenylate-deoxythymidylate) X poly(deoxyadenylate-deoxythymidylate) and covalent poly(deoxyguanylate-deoxycytidylate) X poly(deoxyguanylate-deoxycytidylate) three nitroquinoline adducts were enumerated on the modified DNA. One of them was previously characterized as a C8-guanyl adduct. We proved that the two other are a guanine and an adenine adduct, respectively. A quinoline derivative was identified in the hydrolysates of the in vivo- and in vitro-modified DNAs as 4-aminoquinoline 1-oxide, the origin of which was postulated to be a degradation compound of one (or more) adduct(s). Moreover, the presence of two degradation compounds of the C8-guanyl adduct was shown in mild alkaline conditions. We suspected an imidazole ring-opened form.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed1984

Conformations of poly(dG-dC).poly(dG-dC) modified by the O-acetyl derivative of the carcinogen 4-hydroxyaminoquinoline 1-oxide.

Poly(dG-dC).poly(dG-dC) has been modified by reaction with 4-acetoxyaminoquinoline 1-oxide (Ac-4 HAQO), the ultimate carcinogen of 4-nitroquinoline 1-oxide. The circular dichroism (CD) spectra of the modified and unmodified polymers have been compared under various experimental conditions. The CD spectra were recorded in 1 mM phosphate, 50% (v/v) ethanol, 3.8 M LiCl and 95% (v/v) ethanol, conditions in which poly(dG-dC).poly(dG-dC) adopts the B-, Z-, C- and A-form respectively. In 1 mM phosphate buffer, poly(dG-dC).poly(dG-dC) modified by Ac-4 HAQO seems not to contain regions in the Z-form. Z-form induction could be progressively obtained by the addition of ethanol as follows: in the buffer with about 30% ethanol the modified polymer started to adopt the Z structure, while 40% of ethanol in the buffer was necessary for the unmodified polymer. In the 50% ethanol-1 mM phosphate buffer mixture (v/v), poly(dG-dC).poly(dG-dC) was entirely in the Z-form while poly(dG-dC).poly(dG-dC) modified by Ac-4 HAQO remained partially in the B-form. Enzymatic digestions with the nuclease S1 which is specific of the single-stranded DNA were carried out in order to support the modified poly(dG-dC).poly(dG-dC) CD study conclusions. The role played by the two major adducts on the conformational characteristics of modified polymer is discussed.

Aminoquinolines↗
PubMed1984

Guanyl-C8-arylamination of DNA by the ultimate carcinogen of 4-nitroquinoline-1-oxide: a spectrophotometric titration.

Native and denatured DNAs and polynucleotides were modified by 4-acetoxyaminoquinoline-1-oxide, the ultimate carcinogen of 4-nitroquinoline-1-oxide (4 NQO). The N-( deoxyguanosin -C8-yl)-4-aminoquinoline-1-oxide adduct, the so-called "dG III," was quantified on the DNA and on poly(dG-dC) in absorption spectroscopy, by using a spectral property of dG III, i.e., the variation of the absorption spectrum as a function of the pH. Using the "free-dG III" absorption reference spectra, a simple graphic determination of the percentage of dG III was established by recording the absorption spectra of the 4-acetoxyaminoquinoline-1-oxide-modified polymers. It was found that the dG III adduct accounts for about 30% of the total modification in the case of native modified DNA and poly(dG-dC) and for about 70% in the case of denatured modified DNA.

4-Nitroquinoline-1-oxide↗
PubMed1983

Enzymatic methylation of DNA and poly(dG-dC) X poly(dG-dC) modified by 4-acetoxyaminoquinoline-1-oxide, the ultimate carcinogen of 4-nitroquinoline-1-oxide.

Both the initial velocity and the overall methylation of Ac-4HAQO modified DNA by a calf brain DNA (cytosine-5-)-methyltransferase are increased as compared to native DNA. The affinity of the modified DNA for the enzyme decreases as a function of the extent of the modification. Heat-denatured, single-stranded DNA shows exactly the opposite results: the more it is modified, the less it is methylated. The poly(dG-dC) X poly(dG-dC) modified by 4NQO is as well methylated as the non-modified one. The carcinogen may induce a tertiary structure favouring the 'walking' of the enzyme along the DNA. The hypermethylation caused by this carcinogen could have a significance in gene activity and cellular differentiation.

Aminoquinolines↗
PubMed1983

Identification of 4-acetoxyaminoquinoline from the hydrolysis of 1-acetoxy-4-acetoxyimino-1,4-dihydroquinoline, in vitro and in vivo properties.

4-Acetoxyaminoquinoline (Ac-4-HAQ) (1) was identified as a hydrolysis product of 1-acetoxy-4-acetoxyimino-1,4-dihydroquinoline (diAc-4-HAQO). The reaction allowing the obtention of (1) obeys to a reduction mechanism implying the N1-O cleavage. The carcinogenic properties of (1) observed by Sato et al. (Japan J. Exp. Med., 40 (1970) 475) in mice were studied in rats with the in vivo system we used previously with 4-nitroquinoline-1-oxide (4-NQO) and 4-hydroxyaminoquinoline-1-oxide (4-HAQO). In rats (1) does not covalently bind DNA. It was, therefore, possible to propose an interpretation of the results obtained by Enomoto et al. (Proc. Soc. Exp. Biol. Med., 136 (1971) 1206) who injected diAc-4-HAQO s.c. to mice and rats. Compound 1 could be responsible for the carcinogenic effects observed through the following pathway: (1) should be formed by hydrolysis of diAc-4-HAQO and reactivated by an enzymatic system to N-oxide derivative, the 4-acetoxyaminoquinoline-1-oxide (Ac-4-HAQO), which constitutes an ultimate carcinogen model of 4-NQO.

Aminoquinolines↗
PubMed1983

In vitro DNA reaction with an ultimate carcinogen model of 4-nitroquinoline-1-oxide: the 4-acetoxyaminoquinoline-1-oxide. Enzymatic degradation of the modified DNA.

2-3H-Labelled 4-acetoxyaminoquinoline-1-oxide (Ac-4 HAQO), the ultimate carcinogen model of 4-nitroquinoline-1-oxide, was reacted in vitro with native and denatured DNA. We found that Ac-4 HAQO is 2- to 3-fold more reactive than diAc-4 HAQO, another ultimate carcinogen model of 4 NQO which was previously studied [Galiègue et al. (1980) Biochim. Biophys. Acta, 609, 383-391]. Ac-4 HAQO-modified DNA is thermally destabilized: when 1% of the bases of DNA were modified by Ac-4 HAQO, its melting temperature decreased 1.2 degrees C. Enzymatic degradation of Ac-4 HAQO-modified native and denatured DNA's to nucleosides was performed. The hydrolysates were analyzed, first with a simple chromatographic system, and then by h.p.l.c. The compounds recovered from the modified polymers were characterized by h.p.l.c. and a variation in their respective amounts as a function of the secondary structure of DNA was observed. Especially, the N-(deoxyguanosin-(C8-yl)-4-aminoquinoline-1-oxide, the so called dG III adduct, was recovered from DNA, and its amount was evaluated to be approximately 3.5-fold greater in the case of denatured DNA than in the case of native DNA.

4-Nitroquinoline-1-oxide↗
PubMed1982

In vitro enzymatic recognition of DNA modified by O,O'-diacetyl or O-acetyl derivatives of the carcinogen 4-hydroxyaminoquinoline-1-oxide.

Purified DNA was modified in vitro by 3H-labelled O-acetyl or O,O'-diacetyl-4-hydroxyaminoquinoline-1-oxide (Ac4HAQO or di Ac-4HAQO). It was then subjected to the action of the single-stranded DNA specific nuclease S1 and the digested fractions were analysed. For both types of modified DNA, the release of non-modified nucleotides was faster than the release of modified nucleotides. This result is at variance with that obtained with acetoxy-acetylaminofluorene-modified DNA: in the latter case, the modified nucleotides were preferentially released. The results suggest that the S1 endonuclease can recognize different conformational changes in DNA, which depend on the carcinogen used. The enzymatic activity (or activities) present in Micrococcus luteus cell extracts released ethanol-soluble products from Ac-4HAQO modified DNA.

4-Hydroxyaminoquinoline-1-oxide↗