Some aspects of the metabolism of urethane and N-hydroxyurethane in rodents

Abstract

Urethane and N-hydroxyurethane are interconvertible in C" and C57 mice, prior treatment with 3-methylcholanthrene of urethane stimulated the N-hydroxy-lation of urethane; SKF 525A 2-diethylaminoethyldiphenylpropylacetate hydrochloride inhibited the N-hydroxylation at 24 hr. but stimulated it at 48 hr. after administration. Liver homogenates of CBA and C3H mice, and of Chester Beatty and hooded rats, but not whole-body homogenates of 1-day-old C57/DBA mice or lung homogenate of 3-week-old Chester Beatty rats, metabolized urethane into N-hydroxyurethane in small but definite amounts. Nitrite was detected in the bodies of newborn C57/ DBA hybrid mice treated with lethal doses of urethane or N-hydroxy urethane; nitrite formation from N-hydroxyurethane was stimulated by pretreatment of the animals with 3-methylcholanthrene. The rate of catabolism of N hydroxyurethane by C57/DBA mice was faster in 8 day old than in 1-day-old animals of the same sex, and faster in females than in males of the same age. Liver slices of several species of rats and mice catabolized N-hydroxyurethane at rates that varied with the age and sex of animals of the same species; liver homogenates or micro-somes were less effective than slices from the same liver. The enzyme activity was destroyed by boiling or freezing the liver; it was inhibited by increasing substrate concentration and by urethane, n-butyl carbamate, cyanide, p-benzoquinone or 2,4-dinitrophenol, but not by p-chloromercuri-benzoate or menadione. The catabolism of N-hydroxyurethane by liver slices from adult H-strain rats was not oxygen-dependent. Lung homogenates of 4-week-old female Chester Beatty rats catabolized N-hydroxyurethane at 40% of the rate of liver slices from the same source. O-Acetyl-and O-ethoxycarbonyl N-hydroxyurethane were rapidly deacylated by liver homogenates from adult hooded rats and adult C57 mice, and by human erythrocytes. N- Hydroxyurethane reacted rapidly with pyridoxal phosphate at pH 7.4 and 37[degree]. The rate of decomposition of N-hydroxyurethane in 0.1 N-sodium hydroxide was increased by Ni2+, Cu*+, Mn2+ and[Fe (CN)6]3 and decreased by Cr2+, Zn2+, Co2+, Mg2+, and Fe2+. Attempts to synthesize sutfonates of N-hydroxyurethane gave ethyl hydrogen sulfate, probably via rearrangement of the unstable O-sulfonate.