The urotoxic effects of N,N′-dimethylaminopropionitrile : 2. In vivo and in vitro metabolism

The urotoxicity and metabolism of N,N′-dimethylaminopropionitrile (DMAPN) were investigated in male Sprague-Dawley rats. Animals treated with 525 mg DMAPN/kg or equimolar doses of commercially available potential DMAPN metabolites showed varying levels of urinary retention. About 44% of the administered dose of DMAPN was excreted unchanged in 5 days. β-Aminopropionitrile and cyanoacetic acid were identified as urinary metabolites. The urinary excretion of cyanoacetic acid was nonlinearly proportional to the volume of urine retained in the bladders. In vitro, the metabolism of DMAPN to cyanide, formaldehyde, and cyanoacetic acid was localized mostly in the microsomal fraction of liver, kidney, and urinary bladders. This reaction required NADPH and oxygen for maximal activity. Metabolism of DMAPN was increased in hepatic microsomes obtained from phenobarbital-treated rats (220% of control) and decreased following CoCl 2 treatments (73% of controls). Addition of SKF 525-A to the incubation mixtures inhibited the metabolism of DMAPN to formaldehyde (47–64% of controls). Addition of sulfhydryl compounds (glutathione and cysteine) to the incubation mixtures did not affect the rate of these reactions. These findings indicate that DMAPN is primarily metabolized via a cytochrome P450-dependent mixed-function oxidase system and that the urotoxic effects of DMAPN may be related to this metabolism.