A. Van Der Gen

The role of glutathione conjugation in the mutagenicity of 1,2-dibromoethane

Abstract Two mechanisms for the toxic actions of 1,2-dibromoethane have been postulated, both of which involve biotransformation. The first is oxidation to 2-bromoacetaldehyde, a highly reactive substance, the second a possible direct conjugation to glutathione, giving rise to a reactive half-mustard. It was the purpose of this investigation to determine to what extent these two reactive species are responsible for the mutagenicity of 1,2-dibromoethane. To assess quantitatively the importance of the conjugation to glutathione in vivo, rats were administered single doses of 1,2-dibromoethane; 30–55 per cent of the dose was excreted as mercapturic acid. The conjugation of 1,2-dibromoethane to glutathione was also studied in vitro. Specific activities of the metabolizing systems used in the mutagenicity experiments were determined. The mutagenicity of 1,2-dibromoethane towards Salmonella typhimurium TA100 was considerably enhanced by the addition of 100,000 g supernatant fraction, whereas the addition of microsomes had no effect, indicating that the primary glutathione adduct is responsible for the mutagenic effect. As a model for the mutagenic intermediate, S-2-bromoethyl-N-acetyl-cysteine methyl ester was synthesized. This proved to be a very reactive and highly mutagenic compound, which can be further metabolized and thereby detoxified by glutathione conjugation. A similar phenomenon is likely to occur in the mutagenicity test with 1,2-dibromoethane, where after an initial rise in the number of mutants with increasing amounts of glutathione, the number of mutations decreases again. These results clearly indicate that glutathione conjugation plays an important role in the mutagenicity of 1,2-dibromoethane.

Bio-organic synthesis of optically active cyanohydrins and acyloins

Abstract Chiral acyloins of high optical purity have been obtained in good yields by enzyme catalyzed formation of optically active cyanohydrins, followed by hydroxyl protection and reaction with a Grignard reagent.

Synthesis of Optically Active Cyanohydrins Using Almond Meal

Abstract Asymmetric hydrocyanation of aldehydes was accomplished using almond meal, containing the enzyme oxynitrilase. Optically active cyanohydrins with high levels of enantiomeric purity were obtained following a simple procedure.

Synthesis of optically active silyl protected cyanohydrins

Abstract Mandelonitrile lyase as present in a crude extract of almond flour has been tested for the synthesis of several chiral cyanohydrins. Silylated cyanohydrins of benzaldehyde, 4-methoxybenzaldehyde, piperonal, 5-methylfurfural, butyraldehyde and crotonaldehyde were obtained in good yield and high enantiomeric excess (93%) after treatment with silyl chlorides and imidazole in DMF.

Synthesis of optically active ethanolamines.

Abstract (1 R ,2 S )-2-amino-1-arylethanols of high optical purity have been obtained from optically active tert -butyldimethylsilyl protected cyanohydrins by a Grignard reaction, directly followed by reduction of the intermediate imine. Chiral induction gave a large preponderance of the erythro isomers.

Assessment of the impact of the emission of certain organochlorine compounds on the aquatic environment: Part I: Monochlorophenols and 2,4-dichlorophenol

Abstract The consequences of contamination of the aquatic environment by chlorophenols (2-chlorophenol, 3-chlorophenol, 4-chlorophenol and 2,4-dichlorophenol), have been evaluated by extensive review of the available scientific data. The chlorophenols generally exert moderate toxic effects to mammalian and aquatic life, although toxicity to fish upon long-term exposure may be considerable, as has been found for 2,4-dichlorophenol. Persistence is low when adapted microflora is present, capable of biodegrading these compounds, but may become moderate to high depending on the environmental conditions. This is most pronounced for 3-chlorophenol. Bioaccumulation is expected to be low. A striking feature of these chlorophenols is their strong organoleptic effect.

Synthesis of Optically Active Cyanohydrins Using R-Oxynitrilase in a Liquid-Liquid Biphasic System: Part 1: An Industrially useful Procedure

An improved method is presented for preparing optically active cyanohydrins in high yield and high enantioselectivity, using R-oxynitrilase from almonds as the catalyst in a biphasic water-organic solvent system. Reaction conditions for two representative substates have been studied with respect to conversion, optical purity and enzyme stability.The suitability of the procedure for industrial use was substantiated by the possibility of reusing the enzyme-containing aqueous phase for the synthesis of R-mandelonitrile.

A Horner-Wittig Synthesis of 1-Chlorovinyl Sulfoxides.

1-Chlorovinyl sulfoxides 1 were prepared by Horner-Wittig reaction of the readily accessible [(α-chloro)sulfinylmethyl)diphenylphosphine oxides 2 with aldehydes. Excellent Z-selectivity was observed in most cases.

Carcinogenicity tests of fecapentaene-12 in mice and rats

Fecapentaenes, a class of direct-acting bacterial mutagens, have been isolated from the feces and intestinal tract of humans on a Western meat-containing diet. Two bioassays to test pure fecapentaene-12 (FP-12) for carcinogenicity were performed. FP-12 in dimethylsulfoxide (DMSO) solution was injected i.p. into newborn ICR/MA mice on days 1, 3, 7, 10, 14 and 21. The mice killed after 21 months had neoplasms in liver, lung, glandular stomach and subcutaneous fibrosarcoma. Intrarectal (i.r.) infusion of FP-12 in an aqueous vehicle into male F344 rats for 71 weeks, and killing the rats after 21 weeks more, displayed no evidence of neoplasia associated with FP-12 exposure. The positive control, N-nitrosomethylurea (NMU), given i.r. as 4 2-mg doses in 2 weeks, as expected, yielded multiple colonic neoplasms in less than 11 months. Fecapentaene may exert its effect in bacteria and in newborn mice through the generation of hydroxy radicals. However, adult rodent and human colon may have adequate biochemical defense mechanisms against low level, even continuous exposures to chemicals like FP-12, and thus be at low risk of neoplasia, as was found.

The influence of disulfiram and other inhibitors of oxidative metabolism on the formation of 2-hydroxyethyl-mercapturic acid from 1,2-dibromoethane by the rat

Abstract The mercapturic acid derivative, N- acetyl -S-2- hydroxyethyl - l - cysteine , is a major metabolite of 1,2-dibromoethane in vivo . This compound can be formed via two pathways, both involving a potentially dangerous reactive intermediate. One way involves the intermediacy of bromoacetaldehyde, formed by microsomal oxidation, followed by loss of hydrogen bromide. The second pathway, direct conjugation of 1,2-dibromoethane with glutathione, gives rise to S -2-bromoethyl glutathione. Using several inhibitors of microsomal mixed function oxidases, it was found that under these conditions about 10% of the mercapturic acid derivative formed via direct conjugation. Disulfiram, an inhibitor of aldehyde dehydrogenases, but also of microsomal oxidation, also markedly inhibits the excretion of the mercapturic acid, after administration of a single high dose (1 g/kg) or upon chronic treatment with a low dose (50 mg/kg). The inhibitory effect is maximal after 10 days of chronic treatment. Administration of large amounts of 1,2-dibromoethane (>0.20 nmole/rat) following a single lower dose of disulfiram (125 mg/kg) also leads to a lower excretion of mercapturic acid metabolite a phenomenon associated with a decrease in cytochrome P-450 levels. From these results it is concluded that the enhanced carcinogenic effect of the combination disulfiram (chronic)/1,2-dibromoethane is not caused by bromoacetaldehyde, since its formation is completely inhibited under these conditions, but by S -2-bromoethyl-glutathione, although a role for 1,2-dibromoethane itself cannot be excluded.