The Biosynthesis of 3-Hydroxypropylmercapturic Acid from Cyclophosphamide

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Abstract
1. 3-Hydroxypropylmercapturic acid has been identified in the urine of rats dosed with cyclophosphamide, isophosphamide, and trilophosphamide and was isolated as its dicyclohexylammonium salt from the urine of rats dosed with cyclophosphamide. 2. Rats excreted in their urine 55·5% of the 14C of an i.p. dose (200 mg/kg) of [4-14C]cyclophosphamide during the first 24 h after administration, and a further 6·6% during the subsequent 24 h. Of the total radioactivity excreted during the first 24 h, unchanged cyclophosphamide represented 19·3% or less, 41·6% was due to the major metabolite, carboxyphosphamide, and 3-hydroxypropylmercapturic acid represented 11·9%. The 14C label in the mercapturic acid was located in the S-substituent. 3. 3-Hydroxypropylmercapturic acid was the only sulphur-containing metabolite of cyclophosphamide found in the blood and liver of rats, but 3-hydroxy[14C]propylmercapturic acid and S-(3-hydroxy[14C]propyl)-L-cysteine were tentatively identified in the bile of a rat dosed with [14C]cyclophosphamide (120mg/kg; i.p.). 4. S-(3-Hydroxypropyl)-L-cysteine and 3-hydroxypropylmercapturic acid were detected in the liver of rats dosed with allyl alcohol. 5. Acrolein undergoes a complex reaction with GSH in vitro producing a number of products, the major one of which, after reduction with borohydride, is chromatographically identical to S-(3-hydroxypropyl)glutathione. The reduced product, S-(3-hydroxy-propyl)glutathione and S-(3-hydroxypropyl)-L-cysteine are all metabolized by the rat into 3-hydroxypropylmercapturic acid and two minor metabolites. 6. 3-Hydroxypropylmercapturic acid is converted by the rat into 2-carboxyethylmercapturic acid and one other metabolite. Neither of these metabolites was found in the urine of rats dosed with cyclophosphamide. 7. A possible pathway for the formation of 3-hydroxypropylmercapturic acid from cyclophosphamide is discussed.