Studies on the in vivo formation of acrolein: 3-hydroxy-propylmercapturic acid as an index of cyclophosphamide (NSC-26271) activation.
3-Hydroxypropylmercapturic acid (MCA) has been quantitatively determined in the urine of rats given cyclophosphamide (CP), related antineoplastic agents, allyl alcohol, or acrolein, with a simple procedure involving the use of an amino-acid analyzer. Male rats (300-400 g) injected with CP (50mg [179.1 mumols]/kg of body weight) excreted 16.7 mumols of MCA/kg in their 24-hour urine. Equivalent amounts of isophosphamide produced 9.0; triphosphamide, 16.1; ASTA-5607, 7.2; ASTA-5122, 4.1; and cytoxyl alcohol, 0.4mumols of MCA/kg. From allyl alcohol and acrolein, 26.3 and 19.7 mumols of MCA/kg were obtained respectively. MCA values were directly proportional to drug dose levels. Since acrolein and phosphorodiamidic acid mustard are the toxic decomposition products of aldophosphamide, and acrolein conjugation appears to be the first step for MCA formation values for MCA would reflect active CP levels. The in vitro interaction of acrolein with glutathione, other sulfhydryl compounds, and a few amino acids at concentrations of 0.15 mumols/ml was also studied. The decrease of acrolein's main absorption peak at 209 nm was used to follow its reaction rate. The faster interactions observed were with the sulfhydryl compounds, where a 50% decrease of absorption in interactions with glutathione and cysteine (at pH 7.4 and 23 degrees C) took place in 111 and 30 seconds respectively. Incubation of these adducts at 37 degrees C and 100 degrees C generated acrolein with a maximum recovery yield of 83% at 100 degrees C. Five patients given 1 g of CP iv excreted 6.4-50 mumols of MCA in their urine in 6 hours.
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000652:urine; D000171:Acrolein / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000478:Alkylation; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003520:Cyclophosphamide / Q000378:metabolism*; D005978:Glutathione; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013438:Sulfhydryl Compounds
D000447:Aldehydes; D013438:Sulfhydryl Compounds; D000171:Acrolein; D003520:Cyclophosphamide; D005978:Glutathione; D000111:Acetylcysteine