Role of human CYP2A13 and CYP2F1 in naphthalene bioactivation and toxicity in the lung and nasal mucosa of a CYP2A13/2F1‐humanized Mouse (LB636)

Abstract

The aim of this study is to characterize the expression and activity of CYP2A13 and CYP2F1, two human P450 enzymes expressed preferentially in the respiratory tract. CYP2A and CYP2F enzymes have been reported to metabolize many lung toxicants, including naphthalene (NA). The function of human CYP2A13 and CYP2F1 in NA bioactivation and respiratory tract toxicity was examined in this study using CYP2A13/2F1‐humanized mice and CYP2A13(only)‐humanized mice (on Cyp2abfgs‐null background). In vitro studies indicated that, while the activity in the nasal olfactory mucosa (OM) of the CYP2A13/2F1‐humanized mice was primarily contributed by CYP2A13, the activity in the lung was mainly contributed by CYP2F1. Further in vivo studies were conducted, in order to assess the capabilities of CYP2A13 and CYP2F1 to mediate acute inhalation toxicity of NA, at an NA dose relevant to occupational exposure (10 ppm for 4 h). CYP2A13/2F1‐humanized mice showed greater sensitivity than Cyp2abfgs‐null mice did, to NA‐induced depletion of non‐protein sulfhydryl and occurrence of cytotoxicity (observable by routine histology) in the OM (but not lung), when examined at 2 or 24 h after termination of NA exposure. However, preliminary results showed that the lungs of NA‐treated CYP2A13/2F1‐humanized mice had greater numbers of dye‐permeable (injured) cells than that of NA‐treated Cyp2abfgs‐null mice, in both proximal and distal bronchioles, when examined using an ethidium homodimer incorporation assay, which is more sensitive than routine histology examination. These results demonstrate that both CYP2A13 and CYP2F1 are active toward NA in the lung and OM of the CYP2A13/2F1‐humanized mice, and they play a significant role in NA‐induced toxicity.