Metabolism of α-naphthylthiourea by rat liver and rat lung microsomes

Abstract

α-Naphthylthiourea (ANTU) is metabolized by rat liver and lung microsomes to α-naphthylurea (ANU) and atomic sulfur. A portion of the atomic sulfur formed in this reaction covalently binds to macromolecules of the liver and lung microsomes. Approximately half the atomic sulfur bound to the liver and lung microsomes appears to have reacted with cysteine side chains of the microsomal proteins to form a hydrodisulfide. The loss of cytochrome P-450 and monooxygenase activity seen on incubation of liver microsomes with ANTU is likely the result of the covalent binding of atomic sulfur to cytochrome P-450. The available evidence suggests that the pulmonary toxicity of ANTU results, at least in part, from the covalent binding of a cytochrome P-450 monooxygenase catalyzed metabolite of ANTU to pulmonary macromolecules. This metabolite is most likely atomic sulfur or alternatively, one containing the carbonyl carbon of ANTU. However, it is possible that the binding of both metabolites may be responsible for the lung toxicity.