Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice

BACKGROUND: The potential carcinogenicity of naphthalene (NA), a ubiquitous environmental pollutant, in human respiratory tract is a subject of intense debate. Chief among the uncertainties in risk assessment for NA is whether human lung CYP2A13 and CYP2F1 can mediate NA’s respiratory tract toxicity. OBJECTIVES: We aimed to assess the in vivo function of CYP2A13 and CYP2F1 in NA bioactivation and NA-induced respiratory tract toxicity in mouse models. METHODS: Rates of microsomal NA bioactivation and the effects of an anti-CYP2A antibody were determined for lung and nasal olfactory mucosa (OM) from Cyp2abfgs-null, CYP2A13-humanized, and CYP2A13/2F1-humanized mice. The extent of NA respiratory toxicity was compared among wild-type, Cyp2abfgs-null, and CYP2A13/2F1-humanized mice following inhalation exposure at an occupationally relevant dose (10 ppm for 4 hr). RESULTS: In vitro studies indicated that the NA bioactivation activities in OM and lung of the CYP2A13/2F1-humanized mice were primarily contributed by, respectively, CYP2A13 and CYP2F1. CYP2A13/2F1-humanized mice showed greater sensitivity to NA than Cyp2abfgs-null mice, with greater depletion of nonprotein sulfhydryl and occurrence of cytotoxicity (observable by routine histology) in the OM, at 2 or 20 hr after termination of NA exposure, in humanized mice. Focal, rather than gross, lung toxicity was observed in Cyp2abfgs-null and CYP2A13/2F1-humanized mice; however, the extent of NA-induced lung injury (shown as volume fraction of damaged cells) was significantly greater in the terminal bronchioles of CYP2A13/2F1-humanized mice than in Cyp2abfgs-null mice. CONCLUSION: CYP2F1 is an active enzyme. Both CYP2A13 and CYP2F1 are active toward NA in the CYP2A13/2F1-humanized mice, where they play significant roles in NA-induced respiratory tract toxicity.