Dephenylation of the rubber chemical N-phenyl-2-naphthylamine to carcinogenic 2-naphthylamine: A classical problem revisited

摘要

N-Phenyl-2-naphthylamine ( PBNA) represents an example of a suspected carcinogen that is found negative in mutagenicity and clastogenicity testing as well as in long-term animal carcinogenicity bioassays in several species, but for which a carcinogenic risk cannot be excluded because of its metabolic conversion to the known human carcinogen 2-naphthylamine. Also, epidemiologic studies failed to indicate an elevated bladder cancer risk in humans occupationally exposed to PBNA. The amounts of 2-naphthylamine found in the urine of different species including humans after exposure to PBNA indicate unequivocally that PBNA is dephenylated to some extent. These are not explained by the 2-naphthylamine impurities in technical-grade PBNA. To explain the metabolic dephenylation process, it has been suggested that PBNA is metabolized by cytochrome P-450 (CYP) enzymes to the phenolic derivative 4'-hydroxy-N-phenyl-2-naphthylamine, followed by its further oxidation to the quinone imine, which subsequently hydrolyses to form the dephenylation product 2-naphthylamine. Phenolic metabolites from the initial CYP-mediated activation step are rapidly conjugated. Quantitatively, dephenylation of PBNA to 2-naphthylamine is a minor pathway. The dog represents an animal model that appears to approximate the human metabolism and biological activation of PBNA. Based on published data, a worst-case scenario indicates that about 1% of total PBNA taken up is transferred into 2-naphthylamine. However, in vitro as well as in vivo findings with PBNA may point to a significantly smaller conversion rate, as metabolites anticipated from the metabolism of 2-naphthylamine were not detected so far. The assumption, which may well be an overestimation, is compatible with findings in animal experiments, and explains the lack of direct evidence of carcinogenicity of PBNA in both experimental and epidemiological studies.