1,2-Dichloropropane: investigation of the mechanism of mercapturic acid formation in the rat

Abstract

1. Three mercapturic acid metabolites were identified in the urine of male and female Fischer 344 rats given 1,2-dichloropropane (DCP) orally (100 mg/kg) or by inhalation exposure (100 ppm, 6 h). 2. These compounds (N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxopropyl)-L-cysteine and N-acetyl-S-(1-carboxyethyl)-L-cysteine) were isolated from the urine following acidification and extraction with ethyl acetate. The extracts were derivatized with diazomethane and N,O-bis(trimethylsilyl)trifluoroacetamide and analysed by chemical ionization g.l.c.-mass spectrometry. 3. Further mechanistic studies were carried out with the stable isotope-labelled analogue, D6-DCP (105 mg/kg, orally). Analysis of the resulting mass spectra indicated retention of primarily three deuterium atoms in the 2-hydroxypropyl-mercapturic acid formed from D6-DCP. Similar isotope retention was observed for the 2-oxopropyl-mercapturic acid metabolite. 4. These results do not support a sulphonium ion intermediate in the formation of the 2-hydroxypropyl-mercapturic acid metabolite of DCP. Instead, this metabolite is thought to arise via direct oxidation of DCP, either prior to or following conjugation with glutathione.