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

Lei Li, Sarah Carratt, Matthew Hartog, Nataliia Kovalchuk, Kunzhi Jia, Yanan Wang, Qing Yu Zhang, Patricia Edwards, Laura Van Winkle, Xinxin Ding

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number067004
JournalEnvironmental Health Perspectives
Volume125
Issue number6
DOIs
StatePublished - Jun 1 2017

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Nasal Mucosa
Lung
Olfactory Mucosa
Respiratory System
naphthalene
Bronchioles
Inhalation Exposure
Environmental Pollutants
Lung Injury
Uncertainty
Anti-Idiotypic Antibodies
Histology

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

Cite this

Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice. / Li, Lei; Carratt, Sarah; Hartog, Matthew; Kovalchuk, Nataliia; Jia, Kunzhi; Wang, Yanan; Zhang, Qing Yu; Edwards, Patricia; Van Winkle, Laura; Ding, Xinxin.

In: Environmental Health Perspectives, Vol. 125, No. 6, 067004, 01.06.2017.

Research output: Contribution to journalArticle

Li, L, Carratt, S, Hartog, M, Kovalchuk, N, Jia, K, Wang, Y, Zhang, QY, Edwards, P, Van Winkle, L & Ding, X 2017, 'Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice', Environmental Health Perspectives, vol. 125, no. 6, 067004. https://doi.org/10.1289/EHP844
Li, Lei ; Carratt, Sarah ; Hartog, Matthew ; Kovalchuk, Nataliia ; Jia, Kunzhi ; Wang, Yanan ; Zhang, Qing Yu ; Edwards, Patricia ; Van Winkle, Laura ; Ding, Xinxin. / Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice. In: Environmental Health Perspectives. 2017 ; Vol. 125, No. 6.
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title = "Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice",
abstract = "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.",
author = "Lei Li and Sarah Carratt and Matthew Hartog and Nataliia Kovalchuk and Kunzhi Jia and Yanan Wang and Zhang, {Qing Yu} and Patricia Edwards and {Van Winkle}, Laura and Xinxin Ding",
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T1 - Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice

AU - Li, Lei

AU - Carratt, Sarah

AU - Hartog, Matthew

AU - Kovalchuk, Nataliia

AU - Jia, Kunzhi

AU - Wang, Yanan

AU - Zhang, Qing Yu

AU - Edwards, Patricia

AU - Van Winkle, Laura

AU - Ding, Xinxin

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

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