Biotransformation and some effects of 2-dimethylamino-4-(N-methylanilino)-phenol in dogs.

Abstract

2-Dimethylamino-4-(N-methylanilino)-phenol (MP), an active metabolite of N,N-dimethylaniline-N-oxide in the autocatalytic formation of ferrihemoglobin, reacted quickly in dogs after intravenous injection. A dose of 14C-labeled MP which oxidized 40% of the hemoglobin disappeared from the blood in 20 min. During this period of time MP transferred catalytically electrons from ferrohemoglobin to oxygen, reacted with sulfotransferases to form the sulfuric acid ester, and was covalently bound in blood and other tissues. In the urine, in addition to the sulfuric acid ester of MP (25%), methylamine, dimethylamine, and N-methylaniline were found. Their amount indicated that most of the MP not esterified with sulfuric acid had lost a nitrogen by hydrolysis of the quinonimine. The metabolites which were covalently bound in blood and other tissues disappeared slowly, traces of radioactivity being found in blood and urine 7 days after i.v. injection of MP, 15 mg/kg. The formation of methylamines as well as N-methylaniline from MP in vivo and in blood in vitro proves that the oxidation product of MP, a purple dye, is a resonance hybrid of the two structures 2-dimethylamino-N-methyl-N-phenyl-1,4-benzoquinone-4-imonium and 4-(N-methylanilino)-N,N-dimethyl-1,2-benzoquinone-2-imonium. In addition to ferrihemoglobin MP produced numerous Heinz bodies in red cells and caused hemolytic anemia. After lethal doses necroses in the kidney tubules were found.