N-acetyl-S-(2-hydroxyethyl)-L-cysteine as a potential tool in biological monitoring studies? A critical evaluation of possibilities and limitations.

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.

Identification and quantitative determination of four different mercapturic acids formed from 1,3-dibromopropane and its 1,1,3,3-tetradeutero analogue by the rat.

1,3-Dibromopropane (1,3-DBP) was administered i.p. in doses ranging from 5.6 to 54 mg to male Wistar rats. Four different mercapturic acids, viz. N-acetyl-S-3-bromopropyl-(MA I), N-acetyl-S-3-chloropropyl-(MA II), N-acetyl-S-2-carboxyethyl-(MA III) and N-acetyl-S-3-hydroxypropyl(-1-)cysteine (MA IV) were synthesized and identified as metabolites in urine by g.l.c.-mass spectrometry. 1,1,3,3-Tetradeutero-1,3-dibromopropane was used to study the mechanism of formation of the mercapturic acids in more detail. It was found that in the formation of MA IV a reactive episulphonium ion could be involved. Gas chromatographic quantification of the mercapturic acids (mercapturic acid assay) was correlated with a spectrophotometric thioether determination of the metabolites (thioether test). At doses up to 30 mg of 1,3-DBP, excretion of mercapturic acids was virtually complete in 24 h urine and amounted to about 19% of the dose (11.3% MA I, 4.9% MA II, 2.6% MA III and 0.2% MA IV). From excretion rate curves a half-time t1/2 was calculated as being about 4.5 h. A plateau in the dose-excretion curve was observed at 1,3-DBP doses higher than 40 mg, probably caused by glutathione depletion.