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C Malaveille

Publications and source records attributed to C Malaveille.

At least 91 records · Page 5Linked to original sources
PubMed1982

Quantitative comparisons between carcinogenicity, mutagenicity and electrophilicity of direct-acting N-nitroso compounds and other alkylating agents.

The quantitative relationship between carcinogenicity in rodents and mutagenicity in S. typhimurium was examined using 10 monofunctional alkylating agents, including N-nitrosamides, alkylmethane sulfonates and epoxides. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535, TA100) and in plate and liquid assays. Mutagenic activity was compared with alkylating activity, half-life (solvolysis constant) and carcinogenic activity in rodents (TD50). No correlations between these variables were found. However, there was a good positive relationship between the TD50 values of the carcinogens and the initial ratios of N-7-alkylguanine to 0(6)-alkylguanine formed after reaction with double-stranded DNA in vitro (r = 0.88, p less than 0.01; n = 9). From these results, it is concluded that the N-7/0(6)-alkylguanine ratio is quantitatively related to the carcinogenic activity for this class of compounds and it may therefore be used to predict the carcinogenic potency of new compounds within this class.

Alkylating Agents↗
PubMed1982

Inhibition by specific antibodies of the mutagenicity of aflatoxin B1 in bacteria.

Two anti-aflatoxin B1 antisera, antiserum 'O' and antiserum 'C', were raised against conjugates in which the bovine serum albumin protein carrier was coupled to aflatoxin B1 derivatives at carbon 1 or 8. Their action was investigated in Salmonella thyphimurium assays using a fortified 9000 x g supernatant (S9) of rat liver homogenate or using rat hepatocytes as the metabolic activation system. In all cases, a substantial reduction in mutagenicity was observed: the mutagenicity caused by 12.5 ng aflatoxin B1 was inhibited by 50% with 2 microliters of antiserum 'O' and with 12 microliters of antiserum 'C' when activation was catalysed by rat liver supernatant; the mutagenicity of 3.31 micrograms aflatoxin B1 was inhibited by 50% with 25 microliters of antiserum 'O' in experiments using hepatocytes as the metabolic activation system. Several lines of evidence indicate that the inhibition is caused by specific antibodies. The molar ratios of aflatoxin B2 or aflatoxin G2 to aflatoxin B1 required to reduce by 50% the effect of antisera on aflatoxin B1 mutagenicity were 2.9-76-fold higher than those required to reduce by 50% the tracer antibody binding in radioimmunoassay. Possible mechanisms by which anti-aflatoxin B1 antisera inhibit aflatoxin B1 mutagenicity are discussed.

Aflatoxin B1↗
PubMed1982

Detection of aflatoxins and related metabolites by radioimmunoassay.

Rabbit (outbred albino New Zealand White) antisera have been raised against aflatoxin B1 (AFB1) using as immunogen conjugates in which the hapten was coupled to bovine serum albumin (BSA) either through C1 or C8 with the oxime and the dichloride derivatives of AFB1 as intermediates. Radioimmunoassay (RIA), with [3H]AFB1 as tracer, showed that the antiserum prepared with the conjugate in which BSA was coupled to the AFB1 oxime derivative was highly specific to AFB1, whereas the antiserum raised against the conjugate in which BSA was coupled to AFB1 through the AFB1Cl2 derivative (C-antiserum) cross-reacted to a large extent with other aflatoxins, including aflatoxin M1, an important urinary metabolite of AFB1 in several species including humans. AFB1-related metabolites in the urine of inbred BD IV adult male rats given AFB1 orally at doses from 600 pmol to 385 nmol can easily be followed over 9 days by RIA in which the "cross-reactive" C-antiserum is used. This suggests that similar methodologies could be used for the monitoring of human exposure to AFB1.

Aflatoxin B1↗
PubMed1982

Mutagenic and alkylating activities of 3-methyl-1-phenyltriazenes and their possible role as carcinogenic metabolites of the parent dimethyl compounds.

3-Methyl-1-phenyltriazene and a series of ring-substituted derivatives (4-methylphenyl, 4-chlorophenyl, and 2,4,6-trichlorophenyl), structurally related benzenediazonium fluoborates and phenyl azides, as well as the recently isolated [1-methyl-3-(2,4,6-trichlorophenyl)-2-triazeno]methyl-beta-D-glucopyranoside uronic acid, were studied for their mutagenic activity in Salmonella typhimurium strains. Of these compounds, the 3-methyl-1-phenyltriazene derivatives and 2,4,6-trichlorobenzenediazonium fluoborate were found to be direct-acting mutagens; the glucuronide was active in strain TA 1530 only after deconjugation with beta-glucuronidase. The half-lives of the monomethylphenyltriazenes in vitro were determined and compared with their methylating activity towards 4-(4-nitrobenzyl)pyridine and their mutagenicity. The results are discussed in relation to the possible mechanism of action of the N,N-dimethylphenyltriazenes and their monomethyl derivatives as mutagens and organ-specific carcinogens.

Alkylating Agents↗
PubMed1981

Effect of glutathione and uridine 5'-diphosphoglucuronic acid on mutagenesis by benzo[a]pyrene and aflatoxin B1 in the Salmonella/microsome assay.

In the Salmonella/microsome plate or liquid assay, the addition of glutathione (GSH) and uridine 5'-diphosphoglucuronic acid (UDPGA), both cofactors for GSH-S-transferases or UDPGA-transferases, altered the rat-liver microsome-mediated mutagenesis of benzo[a]pyrene (BP) and aflatoxin B1 (AFB). With either BP or AFB, an increased, unchanged or decreased number of revertant colonies of S. typhimurium was observed, depending on the substrate concentration, the source of rat-liver 9000 X g supernatant (S9), the time of incubation and the type of mutagenicity test (liquid or plate assay). Several factors responsible for quantitative changes in the pattern of BP and AFB metabolites under various assay conditions in vitro, which alter the overall mutagenic activity of the parent compound, are discussed.

Aflatoxins↗
PubMed1981

Mutagenicity studies in Salmonella typhimurium on some carcinogenic N-nitramines in vitro and in the host-mediated assay in rats.

N-Nitrodimethylamine, N-nitrodiethylamine, N-nitromorpholine and their N-nitroso analogs, N-nitrosodimethylamine, N-nitrosodiethylamine, and N-nitrosomorpholine, were tested in Salmonella typhimurium strains TA100 and TA1530. The mutagenicity of all compounds, except N-nitrodiethylamine, was demonstrated in liquid incubation assays in at least one of the tester strains; it required the presence of a postmitochondrial supernatant from the liver of Aroclor-treated rats, reduced nicotinamide adenine dinucleotide phosphate-generating system, and oxygen. When compared on a molar basis with their N-nitroso analogs, N-nitromorpholine was about 10 times less mutagenic and N-nitrodimethylamine about 70 times less mutagenic. Addition of disulfiram to the assays at a final concentration of 0.1 mM efficiently inhibited mutagenesis by all nitro and nitroso compounds; ascorbic acid at a 7.4 mM concentration produced less inhibition. Mutagenic activity of the three nitramines was also determined in the host-mediated assay in rats. After p.o. administration of each of the N-nitramines, cells of S. typhimurium strains TA1530 and TA100 that had been injected i.p. were isolated from the peritoneal liquid after 1, 3, and 6 hr. All three nitramines were found to be mutagenic for strain TA1530 but not for TA100. Mutation frequencies (number of histidine revertants per 10(6) surviving cells) were in the descending order N-nitromorpholine greater than N-nitrodiemethylamine greater than N-nitrodiethylamine. After a p.o. dose of N-nitrodiethylamine to rats, bacteria were also isolated from liver, lungs, and kidneys. Mutation frequency was highest in bacteria recovered from the liver but was not increased in those obtained from lungs and kidneys. The data suggest that carcinogenic nitramines exert their mutagenic effects through the formation of alkylating intermediates.

Animals↗
PubMed1981

[Metabolic activation and the mutagenic properties of carcinogenic N-nitramines in a liquid incubation test].

The study established the mutagenicity of carcinogenic dimethylnitramine and nitromorpholine in a liquid-incubation system using Salmonella typhimurium TA 100 and TA 1530 as indicator, in the presence of hepatic postmitochondrial supernatant obtained from 1254 aroclor-treated rats, oxygen and NADP+--generating system. Synthesis of mutagenic metabolites of nitramines was in correlation with the level of N-dimethylase activity. Ascorbic acid and disulfiram efficiently inhibited intramune-induced mutagenesis. Metabolic activation of nitramines involves (a) conversion of nitramines to nitrosoamines due to reduction of a nitro group, (b) hydroxylation by means of multi-function oxydases, and (c) heterolysis resulting in the formation of an end metabolite which is actually responsible for carcinogenicity and mutagenicity.

Aniline Compounds↗
PubMed1980

Mutagenicity of benzo[a]pyrene 7,8-dihydrodiol and 7,12-dimethylbenz[a]anthracene 3,4-dihydrodiol in S. typhimurium mediated by microsomes from rat liver and mouse skin.

The mutagenic activities of trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP 7,8-diol) and of trans-3,4-dihydroxy-7,12-dimethylbenz[a]-anthracene (DMBA 3,4-diol) towards S. typhimurium TA100 were measured in assays that were carried out on a micro-scale in liquid medium in the presence of microsomal fractions prepared from mouse skin or rat liver. In the presence of an NADPH-generating system, microsomal enzymes converted both diols into mutagens that were probably the respective 'bay-region' diol-epoxides. The rate of the enzyme-catalysed conversion of the BP 7,8-diol into mutagens by microsomal preparations from mouse epidermis was similar to that occurring with microsomes from rat liver. Pretreatment of mice by the topical application of benz[a]anthracene (BA) or 7,12-dimethylbenz[a]-anthracene (DMBA) increased the mutagenic activity of BP 7,8-diol mediated by mouse skin microsomal preparations by 2-fold and this was paralleled by a 4-fold increase in epidermal aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity. The results are discussed in relation to the high susceptibility of mouse skin to polycyclic aromatic hydrocarbon (PAH) carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Carcinogenicity of chloroethylene oxide, an ultimate reactive metabolite of vinyl chloride, and bis(chloromethyl)ether after subcutaneous administration and in initiation-promotion experiments in mice.

Repeated s.c. administration of chloroethylene oxide, a reactive metabolite of the carcinogen vinyl chloride, induced local tumors in mice, with an incidence comparable to that of bis(chloromethyl)ether, a structurally related human and animal carcinogen, when both compounds were applied at maximum tolerated chronically toxic doses; no tumors distant from the injection site were produced. Bis(chloromethyl)ether, chloroethylene oxide, and its rearrangement product chloroacetaldehyde, a highly toxic compound, were further tested in an initiation-promotion experiment. Application to the skin of a single dose of either bis(chloromethyl)ether or chloroethylene oxide, followed by 3-times-weekly applications of 12-O-n-tetradecanoylphorbol-13-acetate for 42 weeks, produced skin tumors in mice; chloroacetaldehyde under comparable conditions produced no increase in benign or malignant tumors. A good correlation between the chemical reactivity, on the basis of hydrolysis constants in aqueous media, and the carcinogenicity of the three compounds was noted. Our results support the hypothesis that epoxidation of the thylenic double bond in vinyl chloride yields an ultimate carcinogenic metabolite, chloroethylene oxide, a highly reactive compound which appears also to be largely responsible for the known genetic changes caused by the parent compound.

Animals↗
PubMed1979

The association of bacterial mutagenicity of hydrocarbon-derived 'bay-region' dihydrodiols with the Iball indices for carcinogenicity and with the extents of DNA-binding on mouse skin of the parent hydrocarbons.

The mutagenic activities of benz[alpha]anthracene, 7-methylbenz[alpha]anthracene, 7,12-dimethylbenz[alpha]anthracene, 3-methylcholanthrene and benzo[alpha]pyrene, together with those of the trans-dihydrodiols derived from these hydrocarbons that would be expected to yield 'bay-region' vicinal diolepoxides on further metabolism have been examined in assays with S. typhimurium TA100 using post-mitochondrial supernatant fractions prepared from the livers of 3-methylcholanthrene-treated rats. Mutagenic activities obtained have been compared with: (a) the extents of reaction with DNA that occur in mouse skin following treatment with these hydrocarbons; (b) the carcinogenicities of the hydrocarbons expressed as Iball indices; (c) their activities as tumour-initiating agents on mouse skin. Close positive associations were found between the microsome-mediated mutagenicities of the dihydrodiols that could yield "bay-region" diol-epoxides and: (a) the extents of reaction with DNA in hydrocarbon-treated mouse skin; (b) the carcinogenic potencies of the parent hydrocarbons; although these correlations are not perfect, the mutagenic activities of the hydrocarbons themselves in microsome-mediated assays with S. typhimurium show no correlation with their extents of DNA binding on mouse skin and a poor correlation with their activities as initiating agents. These comparisons also indicated a statistically-significant positive correlation between carcinogenicity and the in vivo DNA binding on mouse skin treated with the hydrocarbons. Differences in the metabolic pathways by which polycyclic hydrocarbons are activated in vivo and in vitro are discussed in relation to the improved correlations found with the dihydrodiols.

9,10-Dimethyl-1,2-benzanthracene↗