Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism

One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be resp...

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Published inCancer research (Chicago, Ill.) Vol. 42; no. 9; p. 3688
Main Authors Berrigan, M J, Marinello, A J, Pavelic, Z, Williams, C J, Struck, R F, Gurtoo, H L
Format Journal Article
LanguageEnglish
Published United States 01.09.1982
Subjects
Acetylcysteine - pharmacology
Aminopyrine N-Demethylase - metabolism
Animals
Aryl Hydrocarbon Hydroxylases - metabolism
Cyclophosphamide - adverse effects
Cyclophosphamide - metabolism
Cytochrome P-450 Enzyme System - metabolism
Leukopenia - chemically induced
Liver - enzymology
Male
Mercaptoethanol - analogs & derivatives
Mesna - pharmacology
Mixed Function Oxygenases - metabolism
NADPH-Ferrihemoprotein Reductase - metabolism
Oxidoreductases - metabolism
Rats
Rats, Inbred Strains
Urinary Bladder - drug effects
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Summary:One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.
ISSN:0008-5472