1. N-acetyl-S-(2-hydroxyethyl)-L-cysteine as a potential tool in biological monitoring studies? A critical evaluation of possibilities and limitations
N P Vermeulen, J de Jong, E J van Bergen, R T van Welie Arch Toxicol. 1989;63(3):173-84. doi: 10.1007/BF00316366.
In mammalian species, including man, N-acetyl-S-(2-hydroxyethyl)-L-cysteine (2-HEMA) is a common urinary metabolite of a large number of structurally different xenobiotic chemicals. It is a common urinary end product of glutathione pathway metabolism of a variety of chemicals possessing electrophilic properties and, in most cases, also a genotoxic potential. Five different chemically reactive intermediates, with different electrophilic properties, may be involved in the formation of 2-HEMA. An inventory of chemicals known to lead to the formation of 2-HEMA, or based on their chemical structure expected to do so, is presented. Furthermore, an attempt is made to evaluate the possibilities and limitations in terms of the potential use of urinary 2-HEMA as a tool in biomonitoring studies. Two other related, sulfur-containing urinary metabolites, i.e. N-acetyl-(S-carboxymethyl)-L-cysteine and thio-diacetic acid, are proposed as possible alternatives to urinary 2-HEMA. It is suggested that 2-HEMA might be seen as a potentially useful and sensitive signal parameter for the assessment of exposure of animals and man to a variety of electrophilic and therefore potentially toxic xenobiotic chemicals.
2. Urinary N-acetyl-S-2-hydroxyethyl-L-cysteine in rats as biological indicator of ethylene oxide exposure
M Gérin, R Tardif Fundam Appl Toxicol. 1986 Oct;7(3):419-23.
There is no simple method known for the biological monitoring of ethylene oxide exposure. N-Acetyl-S-2-hydroxyethyl-L-cysteine (2-hydroxyethylmercapturic acid) excretion was evaluated as a potential indicator of exposure to this gas. Groups of Sprague-Dawley rats were given iv doses of 1, 10, or 100 mg/kg of ethylene oxide dissolved in water. Urines were collected after 12 and 24 hr. In another experiment groups of Sprague-Dawley rats were exposed by inhalation to concentrations of 1, 5, 10, 25, 50, and 200 ppm of ethylene oxide during a 6-hr period and 24-hr urines were collected subsequently. 2-Hydroxyethylmercapturic acid was analyzed in rat urine after enzymatic deacetylation into S-2-hydroxyethyl-L-cysteine, formation of a fluorescent derivative, and separation from other amino acid derivatives by high performance liquid chromatography. No S-2-hydroxyethyl-L-cysteine was observed in any sample when analysis proceeded without the deacetylation step. 2-Hydroxyethylmercapturic acid, however, was present in the urine of all exposed groups. Doses of 1 and 10 mg/kg were excreted at a fairly constant percentage of the dose, ca. 30% from 0 to 12 hr and 5% from 12 to 24 hr, while at 100 mg/kg the equivalent percentages were 16 and 5%, indicating a possible saturation of glutathione conjugation in the first 12 hr. In inhalation experiments, the amount of 2-hydroxyethylmercapturic acid excreted in 24 hr varied linearly with exposure concentration, averaging 0.27 mumol/ppm. The consistency of the excretion of this metabolite over a wide dose span points to 2-hydroxyethylmercapturic acid as a potential biological indicator of exposure to ethylene oxide.
3. N-acetyl-S-(1-cyano-2-hydroxyethyl)-L-cysteine, a new urinary metabolite of acrylonitrile and oxiranecarbonitrile
I Linhart, J Smejkal, J Novák Arch Toxicol. 1988;61(6):484-8. doi: 10.1007/BF00293695.
Two mercapturic acids, i.e., N-acetyl-S-(1-cyano-2-hydroxyethyl)-L-cysteine (CHEMA) and N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA), were isolated from the urine of rats dosed with four successive doses of oxiranecarbonitrile (glycidonitrile, GN), 5 mg/kg, a reactive metabolic intermediate of acrylonitrile (AN). GC-MS analysis of methylated urine extracts from both AN- and GN-dosed rats showed another mercapturate which was identified as N-acetyl-S-(1-cyanoethenyl)-L-cysteine (1-CEMA) methyl ester using an authentic reference sample. The mass spectrum of this compound was very similar to that of a methylated metabolite of AN tentatively identified by Langvardt et al. (1980) as N-acetyl-3-carboxy-5-cyanothiazane (ACCT). In contrast, no ACCT was found in rats dosed with either GN or AN. Hence, there is no evidence for the formation of ACCT or its isomers in rats dosed with AN or GN. The methyl ester of 1-CEMA is formed artificially by dehydration of CHEMA methyl ester in the injector of the gas chromatograph.
