Buthionine sulfoximine prevents the reduction of the genotoxic activity of maleic hydrazide by soil humic substances in Vicia faba seedlings.

A significant reduction of the genotoxic effects caused by herbicide maleic hydrazide (MH) in Vicia faba seedlings was observed to be induced by a growth step in an organic soil as well as by a pretreatment with highly purified humic substances. In addition, such protective activity was resulted quite similar to that observed when the conditioning pretreatment was carried out with metal salts, so suggesting the involvement of the GSH biosynthesis in determining the protective activity observed. In agreement with this hypothesis, a previous exposure to buthionine sulfoximine (BSO), an inhibitor of the phytochelatins production, through the inhibition of GSH synthesis, prevented the reduction of the genotoxic activity of MH. The findings provide evidence for the involvement of the GSH biosynthesis pathway in determining the antigenotoxic activity revealed and suggest a possible involvement of the phytochelatins in this process. However, yet to be clarified is whether the stimulation of GSH production results as a consequence of a nonspecific influence on the protein synthesis by humic substances or of its direct activation due to the presence, as contaminants, of some heavy metals in both organic soil and humic acids extracts.

An E. coli ada transgenic clone of Nicotiana tabacum var. Xanthi has increased sensitivity to the mutagenic action of alkylating agents, maleic hydrazide and gamma-rays.

Two transgenic clones X3 and X15 of Nicotiana tabacum var. Xanthi, heterozygous in two genes (a1 and a2) for chloroplast differentiation and transformed with the E. coli DNA repair gene ada cloned downstream from the 1' direction of the dual mas promoter, differed in the expression of the ada gene, in the number of copies of integrated T-DNA and in the response to the mutagenic action of alkylating and non-alkylating agents. The X3 genome contained four copies and the X15 genome one copy of T-DNA, nevertheless the expression of the ada gene, measured by the activity of O6-alkylguanine DNA alkyltransferase (ATase), was about six times higher in X15 than in X3. ATase activity in both clones was highest in extracts from callus whereas very low (X15) or no (X3) activity was detected in leaf extracts. This may explain the lack of difference between X15 and non-transformed tobacco (NTX) in the frequency of N-methyl-N-nitrosourea (MNU)-induced somatic mutations in leaves. In contrast, the frequency of somatic mutations in X3 was about 2-5 times higher than in NTX and X15 after the same doses of MNU, methyl methanesulfonate, maleic hydrazide and gamma-rays. Alteration of plant gene(s) essential in mutation pathway(s) by insertion of T-DNA or by somaclonal variation may explain the higher sensitivity of the X3 clone.

Metal-induced genotoxic adaptation in barley (Hordeum vulgare L.) to maleic hydrazide and methyl mercuric chloride.

Presoaked seeds of barley, Hordeum vulgare L., were exposed for 2 h to maleic hydrazide (MH), 5 x 10(-2) M or methyl mercuric chloride (MMCl), 10(-4) M with or without a prior conditioning with MH, 5 x 10(-3) M; MMCl, 10(-5) M; cadmium sulfate (CdSO4), 10(-4) M or zinc sulfate (ZnSO4), 10(-1) M; the interexposure time was 2 h. Subsequently as the seeds germinated a number of endpoints were measured that included mitotic index, mitotic chromosome aberrations and micronuclei (MNC) in embryonic shoot cells fixed at 32, 36, 40, 44, 48 and 52 h of recovery, and seedling height on day 7. The results demonstrated that prior conditioning exposure to MH or metals induced genotoxic adaptation to the subsequent challenge exposure to MH and MMCl. Cadmium-induced genotoxic adaptation against either MH or MMCl challenge exposure was, however, significantly prevented when the presoaked seeds were pre-exposed to buthionine sulfoximine, 10(-3) M for 2 h, thereby providing evidence that the underlying mechanism of genotoxic adaptation possibly involved phytochelatins.

A comparison of Vicia-faba-root S10 and rat-liver S9 activation of ethanol, maleic hydrazide and cyclophosphamide as measured by sister-chromatid exchange induction in Chinese hamster ovary cells.

A comparison of Vicia-faba-root S10 with rat-liver S9 was made in their capacity to bring about, in vitro, the metabolic activation of ethanol, maleic hydrazide (MH) and cyclophosphamide (CP) that can lead to the induction of sister-chromatid exchanges (SCEs) in CHO cells. When NADP was a cofactor in the S9 mix, ethanol, MH and CP all induced an increase of SCEs with rat-liver S9. With Vicia-root S10, however, ethanol induction of SCEs was very weak and no effect at all was observed with MH and CP. When NAD was a cofactor in the S9 mix, Vicia-root S10 activated ethanol and produced an increase in SCEs.

A review of environmental and health risks of maleic hydrazide.

The cellular metabolism, acute toxicity, mutagenicity, and carcinogenicity of maleic hydrazide have been reviewed. It seems that this chemical is a mutagen and a carcinogen in cell cultures and animals, but no evidence is available on human carcinogenicity regardless of population exposure in manufacturing, agriculture, and the food chain (i.e., potatoes, potato chips). Because of the level of exposure of the general public to this compound, an epidemiologic survey should be conducted to ascertain possible human health effects. Long-term feeding experiments should be conducted in several animal species to establish whether maleic hydrazide is carcinogenic by this route. Biotransformation and pharmacokinetic studies should be undertaken to obtain better understanding of the chemical's metabolism and excretion. Such investigations would firmly establish whether the tolerance for maleic hydrazide should remain unchanged or whether the use of the compound should be more restricted.

Cytotoxic effects of maleic hydrazide.

Since 1950, maleic hydrazide (MH) has been introduced into agriculture as a major commercial herbicide and a depressant of plant growth in numerous circumstances such as suppression of sprouting of vegetables and stored food crops, control of sucker growth on tobacco plants, ratardation of flowering and prolongation of dormancy period. Since 1951 MH has been known as an effective chromosome-breaking agent in higher plants, in sharp contrast with its low effect on the chromosomes and general health of tested mammals. The selectivity of action of MH in plants and animals was obviously the main reason of low interest devoted to the chemical by people working the field of environmental mutagenesis. In early works the inhibitory effects of MH on plant growth were mainly considered to result from the suppression of plant metabolism (inhibition of enzymic activity) and interference of the compound with plant hormones and growth regulators. More recently, numerous experiments performed with various plant species have shown that MH acts as an inhibitor of the synthesis of nucleic acids and proteins. Similar results have been obtained with animal tumour cells. The chromosome-breaking effect of MH on plant chromosomes resembles very closely the chromosome-breaking properties of alkylating agents and other mutagenic compounds such as mitomycin C. MH-induced chromosomal aberrations have also been recorded in grasshoppers, fish and mice, although tests with some mammalian cell lines gave negative results. Among higher plants, selective sensitivity to the toxic effects of MH is well proved. This phenomenon seems to be due to the differential ability of various plant species to detoxicate the chemical. Plants can break down MH into several products, one of which, hydrazine, is a well-known mutagen and carcinogen. MH does not seem to be toxic to bacteria and fungi. The compound is degraded by soil microflora and hence can be utilized as a source of nitrogen nutrition. MH proved to be of low toxicity to mammals, but in some instances it decreased the fertility of rats. The reported carcinogenic effects of MH in mice and rats raise the question of its risks to man.

Maleic hydrazide: should the Delaney amendment apply to its use?

The chemistry, metabolism, toxicology, mutagenicity, and carcinogenicity of maleic hydrazide have been reviewed. There is little doubt that this chemical is a mutagen and a carcinogen in cell cultures and animals, but no evidence is available on human carcinogenicity regardless of population exposure in manufacturing, agriculture, and the food chain (i.e., potato chips). An epidemiology survey should be conducted to ascertain possible human carcinogenicity in these populations. A long-term ingestion experiment should be conducted in several animal species to establish whether maleic hydrazide is carcinogenic by this route. Biotransformation studies should be undertaken along with pharmacokinetic studies to obtain a better understanding of the chemical's metabolism and excretion. Such investigations would firmly establish whether the tolerance formaleic hydrazide should remain or whether the use of the compound should be banned under the Delaney Amendment.

Tumorigenic agents in unburned processed tobacco: N-nitrosodiethanolamine and 1,1-dimethylhydrazine.

Two tumorigenic agents, N-nitrosodiethanolamine and 1,1-dimethylhydrazine, have been isolated from tobacco for the first time. The former, a reportedly weak hepatic carcinogen in rats, varied in amounts from a low of 0.1 ppb in flue-cured tobacco not treated with the herbicide MH-30, to a high of 173 ppb in Burley tobacco to which the herbicide had been applied prior to harvesting. MH-30 (maleic hydrazide) used by farmers to remove 'suckers' from tobacco plants, is commonly formulated as the diethanolamine salt. 1,1-Dimethylhydrazine, reported to induce tumors in mice, ranged in amounts from 60 to 147 ppb, except in the case of Burley tobacco where none was detected (detection limit: 0.1 ng). The source of the nitrosamine in the tobacco appears to be the MH-30, whereas that of dimethylhydrazine has not been determined.