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C Malaveille

Publications and source records attributed to C Malaveille.

At least 109 records · Page 6Linked to original sources
PubMed1979

Metabolic and mutagenicity studies on DDT and 15 derivatives. Detection of 1,1-bis(p-chlorophenyl)-2,2-dichloroethane and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (kelthane acetate) as mutagens in Salmonella typhimurium and of 1,1-bis(p-chlorophenyl) ethylene oxide, a likely metabolite, as an alkylating agent.

Using a novel in vitro technique, whereby microsomal enzymes were embedded in an agar layer to prolong their viability, 1,1-bis(p-chlorophenyl) ethylene(DDNU), a mammalian metabolite of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), was converted by microsomal mono-oxygenases of mouse liver into 1,1-bis(p-chlorophenyl)-1,2-ethanediol (DDNU-diol). The putative epoxide intermediate, 1,1-bis(p-chlorophenyl)ethylene oxide (DDNU-oxide), a new compound, was synthesized; it showed weak alkylating activity with 4-(4-nitrobenzyl)pyridine but was not mutagenic in Salmonella typhimurium strains TA100 and TA98. DDT and 13 of its metabolites or putative synthetic derivatives, including 1,1-bis(p-chlorophenyl)-2,2-dichloroethylene (DDE), 1 1,1-bis(p-chlorophenyl)-2-chloroethylene (DDMU), 1,1-bis(p-chlorophenyl)-2-chloroethane (DDMS)-DDNU, 2,2-bis(p-chlorophenyl)ethanol (DDOH), bis(p-chlorophenyl)acetic acid (DDA) and 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethanol (Kethane), caused no mutagenic effects in S. typhimurium strains TA100 or TA98, either in the presence or absence of a mouse-liver microsomal fraction. 1,1-Bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (Kelthane acetate) was a direct-acting mutagen in strain TA100, whereas 1,1-bis(p-chlorophenyl)-2,2-dichloroethane (DDD) was mutagenic in TA98, only in the presence of a mouse-liver microsomal system. The results are discussed in relation to possible pathways whereby DDT is activated to mutagenic and/or carcinogenic metabolites.

Alkylation↗
PubMed1979

Some factors determining the concentration of liver proteins for optimal mutagenicity of chemicals in the Salmonella/microsome assay.

In plate assays in the presence of S. typhimurium TA100 and various amounts of liver 9000 X g supernatant (S9) from either untreated, phenobarbitone- (PB) or Aroclor-treated rats, the S9 concentration required for optimal mutagenicity of aflatoxin B1 (AFB) depended both on the source of S9 and on the concentration of the test compound. In these assays, the water-soluble procarcinogen, dimethylnitrosamine (DMN) was mutagenic in S. typhimurium TA1530 only in the presence of a 35-fold higher concentration of liver S9 from PB-treated rats than that required for AFB, a lipophilic compound. In liquid assays, a biphasic relationship was observed in the mutagenicities in S. typhimurium TA100 of benzo[a]pyrene (BP) and AFB and the concentration of liver S9. For optimal mutagenesis of BP, the concentration of liver S9 from rats treated with methylcholanthrene (MC) was 4.4% (v/v); for AFB it was 2.2% (v/v) liver S9 from either Aroclor-treated or untreated rats. At higher concentrations of S9 the mutagenicity of BP and of AFB was related inversely to the amount of S9 per assay. The effect of Aroclor treatment on the microsomemediated mutagenicity of AFB was assay-dependent: in the liquid assay, AFB mutagenicity was decreased, whereas in the plate assay it did not change or was increased. As virtually no bacteria-bound microsomes were detected by electron microscopy, after the bacteria had been incubated in a medium containing 1-34% (v/v) MC-treated rat-liver S9, it is concluded that, in mutagenicity assays, mutagenic metabolites generated by microsomal enzymes from certain pro-carcinogens have to diffuse through the assay medium before reaching the bacteria. Thus the mutagenicity of BP was dependent on both the concentration of rat-liver microsomes and that of total cytosolic proteins and other soluble nucleophiles such as glutathione. At a concentration of 4.4% (v/v) liver S9, the mutagenicity of BP was about 3.6 times higher than in assays containing a 4-fold higher concentration of cytosolic fraction. Studies on the glutathione-dependent reduction of BP mutagenicity in plate assays has shown that, in the presence of liver S9 concentrations greater than that required for optimal mutagenicity, the reduction in mutagenicity was related directly to the concentration of liver S9. Thus, in the Salmonella/microsome assay, when the concentration of rat-liver S9 was increased over and above the amount required for the optimal mutagenicity of BP, the mutagenic metabolites of BP were inactivated (by being trapped with cytosolic nucleophiles and/or by enzymic conjugation with glutathione); this effect increased more rapidly than their rate of formation. The concentration of liver S9 for optimal mutagenicity of test compounds requiring activation catalyzed by mono-oxygenases seems, therefore, to be related to the departure from linearity of the relationship between the rate of formation of mutagenic metabolites and the concentration of liver S9.

Aflatoxins↗
PubMed1979

Critical importance of microsome concentration in mutagenesis assay with V79 Chinese hamster cells.

For optimum mutagensis in V79 Chinese hamster cells, the amount of liver postmitochondrial fraction in the assay was found to be of critical importance, depending on the chemicals being tested. Benzo[a]pyrene (BP) required lower (1-5%) concentrations of the liver 15 000 X g supernatant (S15) from methylcholanthrene pretreated rats for a maximum induction of cytotoxicity and mutagenicity, as determined by 8-azaguanine- and ouabain-resistance. A sharp peak of mutagenicity and cytotoxicity was induced by 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (7,8-diol BP) at a concentration of 1% of the S15 fraction. Little or no response was induced by these compounds with the S15 concentrations of more than 10%. Similarly, aflatoxin B1 induced a sharp peak of mutagenicity and cytotoxicity at a concentration of 2% of the liver S15 fraction from Aroclor-pretreated rats. Under the same condition, non-carcinogenic aflatoxin G2 did not induce cytotoxicity and mutagenicity. Analysis of BP metabolites by high-pressure liquid chromatography indicates that with the 30% S15 fraction, more than 80% of BP was metabolized during the first 15 min, while with the 2% S15 fraction, 7,8-diol BP increased continuously throughout the 120-min incubation period, suggesting a strong metabolic competition to rapidly remove BP and 7,8-diol BP with a high concentration of the S15. In contrast with these compounds, N-nitrosodimethylamine induced mutagenicity and cytotoxicity which increased linearly in proportion to the increasing amount of the S15 fraction from phenobarbitone- and Aroclor-pretreated rats. Various nitrosamines with different lipophilicity were examined at a high (30%) and low (2%) concentration of the S15 fraction from Aroclor-pretreated rats, in which ratios of mutation frequencies at 30% and 2% correlated inversely with lipophilicity of the compound. This result suggests that the lipid solubility of test compounds may be one factor which determines the concentration of post-mitochondrial supernatant for optimum mutagenesis.

Aflatoxins↗
PubMed1978

Ingested mutagens from opium and tobacco pyrolysis products and cancer of the oesophagus.

Substances which are commonly sucked or chewed in two areas where the incidence of oesophageal cancer is high, the Transkei and north-east Iran, were tested in bacterial mutagenicity assays. Pyrolysed substances, opium dross in north-east Iran and tobacco pipe residues in the Transkei, displayed mutagenic activity in Salmonella typhimurium strains TA98 and TA100 in the presence of rat liver microsomes.

Administration, Oral↗
PubMed1978

High mutagenicity of N-(alpha-acyloxy)alkyl-N-alkylnitrosamines in S. typhimurium: model compounds for metabolically activated N,N-dialkylnitrosamines.

A series of N,N-dialkylnitrosamines (alkyl means methyl, ethyl, n-propyl, n-butyl or tert-butyl group) mono-substituted at the alpha-carbon with an acetoxy group, were tested for their mutagenic action in Salmonella typhimurium TA1530 in the presence or absence of a rat-liver supernatant from 9000 X g. The presumed released of methyl, ethyl, n-butyl and n-propyl carbonium ions from the corresponding alpha-acetoxy derivatives, either by enzymic cleavage or by non-enzymic hydrolysis of the ester group, caused high mutagenicity in the bacteria. As has been demonstrated for certain alpha-acetoxy compounds, the mutagenicity of these compounds was inversely related to their half-lives in aqueous media. N-(Acetoxy)methyl-N-tert-butylnitrosamine and a beta-acetoxy derivative of N,N-diethylnitrosamine were not mutagenic either in the presence or in the absence of hydrolysing rat-liver enzymes. These results support the hypothesis that alpha-carbon hydroxylation is one mechanism involved in the metabolic activation of N,N-dialkylnitrosamines.

Genetic Techniques↗
PubMed1978

Absence of mutagenicity of praziquantel, a new, effective, anti-schistosomal drug, in bacteria, yeasts, insects and mammalian cells.

Praziquantel (Embay 8440, Droncit) a new, effective anti-schistosomal drug, was tested in various short-term assays that have shown a predictive value for the detection of potential carcinogens. Indicator organisms S. typhimurium strains, S. pombe, S. cerevisiae, cultured V79 Chinese hamster cells or human heteroploid cells and Drosophila melanogaster were treated with Praziquantel. The induction of reverse and forward mutations, mitotic gene conversions, X-linked recessive lethals, sister-chromatid exchanges and unscheduled DNA-repair synthesis was scored; rodent-liver microsome-, cell- and host-mediated assays were also performed. Hycanthone, another schistosomicide was included as a positive control. The absence of a genetic activity of Praziquantel uniformly observed in such a battery of tests (i) confirms the assumption that the anti-schistosomal effectiveness of this drug is not related to the mutagenic activity and (ii) should encourage the implementation of extended clinical and field trials.

Animals↗
PubMed1977

Factors for efficiency of the Salmonella/microsome mutagenicity assay.

Factors were studied which modify the enzymatic capacity of mouse liver microsomal mixed-function oxidase to convert vinylidene chloride (1.1-dichloroethylene) (VDC) into mutagens in the Salmonella/microsome mutagenicity test. A microsomal fraction incorporated in soft agar layer converted VDC into mutagens during 7 h at a constant rate; these were detected with S. typhimurium TA100. In absence of VDC the enzymatic activity declined gradually to nil after 14 h of incubation at 37 degrees C. The presence of EDTA greatly enhanced the microsome-mediated mutagenicity of VDC and led to prolonged enzymatic viability, but only when liver fractions from phenobarbitone (PB) pretreated mice were used. The efficiency of the plate incorporation assay for the detection of mutagens is discussed in comparison with assays in liquid suspension.

Animals↗
PubMed1977

Mutagenicity of isomeric diol-epoxides of benzo[a]pyrene and benz[a]anthracene in S. typhimurium TA98 and TA100 and in V79 Chinese hamster cells.

Pairs of isomeric vicinal diol-epoxides derived from benzo[a]pyrene 7,8- and 9,10-dihydrodiols and from benz[a]anthracene 8,9-dihydrodiol were tested for their abilities to revert salmonella typhimurium strains TA98 and TA100 to histidine prototrophy and to induce the formation of 8-azaguanine- or of ouabain-resistant V79 Chinese hamster cells. All six diol-epoxides were active in both bacterial strains, but 7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (the syn isomer) was considerably more mutagenic than the other diol-epoxides. Within the three pairs of stereo-isomeric diol-epoxides, the ratio of the mutagenic potencies of the syn over the related anti isomers varied bothwith the chemical structure and the bacterial strain. The half lives of hydration of these diol-epoxides at pH 7.4 were inversely related to their mutagenic potencies in bacteria. In V79 cells, the two benzo[a]pyrene 7,8-diol 9,10-oxides were mutagenic and the anti isomer was more active than the syn isomer; a reversed order of mutagenic potency with these stereo isomers was observed in S. typhimurium. The other four diol-epoxides were non-mutagenic in V79 cells at the concentrations tested.

Benz(a)Anthracenes↗
PubMed1977

Short-term tests and mycotoxins.

Naturally-occurring fungal metabolites, such as aflatoxins and sterigmatocystin, are specific examples of toxic and hepatocarcinogenic environmental contaminants which are active in Fish, Birds, Mammals and, probably, Man. The biological potency of these substances has led to a search for other carcinogenic fungus-derived products. As screening techniques for selecting compounds to be tested for their genetic and carcinogenic potency in animals, various short-term tests can be currently utilized. The use of mutagenesis, DNA repair, chromosomal aberrations, cell transformation, cytological alterations and reaction with nucleic acids in vivo or in vitro as end-points in short-term tests to detect potential chemical carcinogens will be presented. Based on recent data in the literature and from our own research activities, 2 major aspects of various short-term tests will be critically reviewed: a. their predictive value, in order to assess the possible carcinogenic risk of mycotoxins, and b. their utility to investigate the mechanism of metabolic activation of these chemicals in Mammals and in Man.

Animals↗
PubMed1977

Comparative electrophilicity, mutagenicity, DNA repair induction activity, and carcinogenicity of some N- and O-acyl derivatives of N-hydroxy-2-aminoflourene.

N-Myristoyloxy-N-acetyl-2-aminofluorene, N-acetoxy-N-myristoyl-2-aminofluorene, N-myristoyloxy-N-myristoyl-2-aminofluorene, and N-hydroxy-N-myristoyl-2-aminofluorene each yielded a high incidence of sarcomas in male rats within 5 to 7 months after s.c. injection of 64 micronmoles in divided doses. N-Acetoxy-N-acetyl-2-aminofluorene and N-hydroxy-2-acetylaminofluorene, although potent carcinogens at the s.c. site, were less active than the above derivatives with a myristoyl substituent. N-Sulfonoxy-N-acety--2-aminofluorene (purity larger than or equal to 70%) had little or no carcinogenic activity when administered in large amounts by s.c. injection to rats. The low incidence of tumors could have resulted from N-hydroxy-2-acetylaminofluorene or other decompostion products of the N-sulfonozy derivative. Each of the N-acetoxy and N-myristoyloxy derivatives of N-acetyl-2-aminofluorene and of N-myristoyl-2-aminofluorene showed electrophilic activity toward methionine; N-acetoxy-N-acetyl-2-aminofluorene was the most reactive and N-myristoyloxy-N-myristoyl-2-aminofluorine was the least reactive. Each of these esters also induced unscheduled tritiated thymidine incorportation in nondividing cultured human fibroblasts and thus appeared to induce lesions in DNA that lead to repair synthesis. EACH OF THE N-acetoxy derivatives was highly mutagenic for Salmonella typhimurium strains TA98 and TA1538 without tissue activation; neither N-myristoyloxy derivative was mutagenic under these conditions. While there was a qualitative correspondence between several of the above activities of these 2-aminofluorene derivatives, the quantitative differences and the lack of detectable mutagenicity of the 2N-myristoyloxy derivatives for S. typhimurium indicate the need for multiple short-term tests in the qualitative prediction of potential carcinogenic activity.

Animals↗
PubMed1976

Mutagenicity of beta-oxidized N,N,-di-n-propylnitrosamine derivatives in S. typhimurium mediated by rat and hamster tissues.

The relative abilities of liver, kidney and lung fractions from untreated or phenobarbitone-pretreated rats and hamsters to convert N,N-di-n-propylnitrosamine and several beta-oxidized synthetic putative intermediates into mutagens was quantitatively compared in a tissue-mediated mutagenicity assay with S. typhimurium TA 1530 in vitro. With one exception, namely, N,N-di(2-acetoxy-n-propyl)nitrosamine, liver was the most active tissue from hamsters; in rats also, only liver fractions were able to activate some nitroso-compounds to mutagens. The highest enzyme-mediated mutagenicities were observed with N-2-hydroxy-n-propyl-N-n-propylnitrosamine, N,N-di-n-propylnitrosamine and N,N-di(2-acetoxy-n-propyl)nitrosamine. Hamster lung tissue converted N,N-di-n-propylnitrosamine, N-2-hydroxy-n-propyl-N-n-propylnitrosamine and N,N-di(2-acetoxy-n-propyl)nitrosamine into mutagens; activity with the latter compound was greater with lung tissue than with liver tissue when untreated animals were used. N-methyl-N-n-propylnitrosamine was mutagenic in the presence of hamster liver fraction but less so than N,N-di-n-propylnitrosamine. The results of the mutagenicity assays using various tissues are qualitatively compared to sites of tumour formation in rats and hamsters by these N-nitrosamines.

Animals↗
PubMed1976

Rat and mouse tissue-mediated mutagenicity of ring-substituted 3,3-dimethyl-1-phenyltriazenes in Salmonella typhimurium.

3,3-Dimethyl-1-phenyltriazene and a series of ring-substituted derivatives (X-phi-N=N-N-(CH3)2:X=substituent(s); phi=phenyl) were tested for their mutagenic and toxic action upon Salmonella typhimurium G-46 in a liquid incubation system containing 9000 g tissue supernatants and an NADPH-generating system. The compounds could be grouped into four classes according to their toxicity and mutagenicity after 1 h incubation at 37 degrees C at a concentration of 5 mM in the presence of liver supernatant fractions from phenobarbitone-pretreated mice. When a liver supernatant from untreated mice was compared with one from phenobarbitone-pretreated animals, the mutagenic effect of a series of triazenes (with X=H; 4-chloro; 4-chloro; 4-bromo; 2,4,6-trichloro) in vitro was enhanced twice to ten times. The toxicity of triazenes with X=4-methoxy or 4-acetamido was strongly decreased by a liver fraction from phenobarbitone-pretreated mice in the presence of an NADPH-generating system. With 3,3-dimethyl-1-phenyl-triazene, rat liver fractions caused a lower enzyme-mediated mutagenicity in S. typhimurium G-46 than those of mouse liver, whereas a 9000 g supernatant from brain, a major target organ for the carcinogenic action of certain triazenes, was unable, in either species, to generate metabolites mutagenic for S. typhimurium G-46.

Animals↗
PubMed1976

Comparative mutagenicity of N-nitrosamines in a semi-solid and in a liquid incubation system in the presence of rat or human tissue fractions.

The rat liver microsome-mediated mutagenicities of a series of N-nitrosodialkylamines and heterocyclic N-nitrosamines were determined in a liquid incubation system using Salmonella typhimurium TA1530. The influence on mutation frequency of the concentration of co-factors for mixed-function oxidase and composition and molarity of the buffer was investigated, using N-nitrosomorpholine as substrate. The mutagenicity of the N-nitroso compounds in the liquid incubation system under optimal reaction conditions at equimolar concentration was compared quantitatively with that obtained in a soft-agar incorporation assay. N-Nitrosodi-n-pentylamine and N-nitrosodi-n-butylamine showed no enzyme-mediated mutagenicity in the liquid incubation system, and metabolically activated N-nitroso-dimethylamine and N-nitroso-diethylamine showed negligible mutagenic activity in the soft-agar assays. In contrast with these results with the N-nitrosodialkylamines, the mutagenic effects of heterocyclic N-nitrosamines were similar in the liquid incubation system and in soft-agar incorporation assays. The heterocyclic N-nitrosamines showed rat-liver microsome-mediated mutagenicity in the following descending order: N-nitrosomorpholine greater than N-nitrosopyrrolidine greater than N-nitrosopiperidine greater than N-nitroso-N'-methylpiperazine. Seven human liver specimens converted all heterocyclic N-nitrosamines into mutagens; this activity was similar to that of rat liver, except that for N-nitroso-N'-methylpiperazine, fractions from three human liver biopsies were three to 30 times more active than those from untreated rats. The specific reversion of S. typhimurium TA1530 to histidine prototrophy provides experimental evidence that all the N-nitrosamines studied were converted by liver microsomal enzymes into monofunctional alkylating agents.

Animals↗
PubMed1976

Mutagenicity and metabolism of vinyl chloride and related compounds.

The various adverse biological effects of vinyl chloride appear to be dependent upon the metabolic conversion of this compound into chemically reactive metabolites. The metabolism of vinyl chloride in mammals and in man, including the formation of monochloroacetic acid and some identified sulfur conjugates is reviewed. Hepatic microsomal mixed function oxidases from rats, mice, and humans were equally effective in transforming vinyl chloride into alkylating agents in vitro. Two of the enzyme reaction products, i.e., chloroethylene oxide and 2-chloroacetaldehyde, showed potent genetic activity in microorganisms and Chinese hamster V79 cells. The role of liver microsomal enzymes in the generation of electrophilic mutagenic vinyl chloride metabolites is discussed.

Animals↗