The metabolism of 3-chloro,- 3-bromo- and 3-iodoprpan-1,2-diol in rats and mice

Abstract

1. The metabolism of the 3-halopropan-1,2-diols (alpha-halohydrins) has been investigated in rats and mice. Apart from 3-chloropropan-1,2-diol (I), of which some 10% is excreted unchanged by both species, the compounds are completely degraded following intraperitoneal administration. 2. The alpha-halohydrins are detoxicated by conjugation with glutathione and produce two urinary metabolites, isolated and identified as S-(2,3-dihydroxypropyl)cysteine (VII) and the corresponding mercapturic acid N-acetyl-S-(2,3-dihydroxypropyl)cysteine (VIII). 3. When incubated with rat liver supernatant, the compounds do not conjugate with glutathione and their general chemical reactivity suggests that they react via a common intermediate proposed to be glycidol (2,3-epoxypropanol, IV). As the epoxide produces the same urinary metabolites as the alpha-halo-hydrins, and conjugates with glutathione either with or without liver supernatant to form the primary metabolite S-(2,3-dihydroxypropyl)glutathione (VI), glycidol is also proposed to be the reactive intermediate in vivo. 4. The role of epoxides in intermediary metabolism is discussed.

PIP: The metabolism of the 3-halopropan-1, 2-diols (alpha-halohydrins) was studied in rats and mice. The compounds were completely degraded after intraperitoneal administration, with the exception of 3-chloropropan-1, 2-diol, 10% of which was excreted unchanged. The alpha-halohydrins were detoxicated by conjugation with glutathione, resulting in urinary metabolites, S-(2,3-dihydroxypropyl)cysteine and th e corresponding mercapturic acid, N-acetyl-S-(2,3-dihydroxypropyl)cysteine. The compounds did not conjugate with glutathione when incubated with rat liver supernatant. G lycidol (2,3-epoxypropanol) is thought to be the common intermediate for the chemical reactivity of the compounds. Glycidol is also proposed to be the in vivo reactive intermediate, since the epoxide produces the same urinary metabolites as the alpha-halohydrins, and conjugates with glutathione, with or without liver supernatnat, to form S-2,3-dihydroxypropyl) glutathione. The intermediary metabolic role of the epoxides is discussed.