Metabolic fate of omega-1 and omega-2 oxidized N-nitrosodibutylamines in the rat.

Abstract

Of the three metabolic oxidation pathways of N-nitrosodibutylamine (NDBA) demonstrated in vivo, omega oxidation is responsible for the induction of bladder tumors, while omega-1 and omega-2 oxidations are considered to be associated with the induction of liver tumors by NDBA. The metabolic fate of the following five NDBA derivatives was investigated in the rat in order to elucidate further the metabolic characteristics of NDBA in relation to its hepatocarcinogenic activity: N-nitroso-N-(3-hydroxybutyl)butylamine (NHBBA-3), N-nitroso-N-(3-oxobutyl)butylamine (NOBBA-3), N-nitroso-N-(2-hydroxybutyl)butylamine (NHBBA-2) and N-nitroso-N-(2-oxobutyl)butylamine (NOBBA-2), which are involved in the omega-1 and omega-2 oxidation pathways of NDBA, and N-nitroso-N-(2-oxopropyl)butylamine (NOPBA), a minor urinary metabolite of NDBA. By characterization of the urinary metabolites, NHBBA-3 and NHBBA-2, primary metabolites of NDBA, were shown to undergo further oxidative metabolic transformation via NOBBA-3 and NOBBA-2, respectively, although conjugation with glucuronic acid to afford the glucuronides was demonstrated to be their principal metabolic pathway. The principal urinary metabolite of NOBBA-2 as well as NOBBA-3 was N-nitroso-N-(carboxymethyl)butylamine, while reduction of the oxo group followed by glucuronidation was found to be a minor metabolic pathway. The glucuronide of N-nitroso-N-(2-hydroxypropyl)butylamine was the principal metabolite of NOPBA, N-nitroso-N-(carboxymethyl)butylamine being a secondary metabolite. The hepatocarcinogenic activity of the three oxo compounds (NOBBA-3, NOBBA-2 and NOPBA) in relation to that of NDBA is discussed from the metabolic point of view.