In vitro airway models from mice, rhesus macaques, and humans maintain species differences in xenobiotic metabolism and cellular responses to naphthalene.

Details

• Personal Author:
  Ding X ; Kelty JS ; Kovalchuk N ; Uwimana E ; Van Winkle LS ; Yin L
• Description:
  The translational value of high-throughput toxicity testing will depend on pharmacokinetic validation. Yet, popular in vitro airway epithelia models were optimized for structure and mucociliary function without considering the bioactivation or detoxification capabilities of lung-specific enzymes. This study evaluated xenobiotic metabolism maintenance within differentiated air-liquid interface (ALI) airway epithelial cell cultures (human bronchial; human, rhesus, and mouse tracheal), isolated airway epithelial cells (human, rhesus, and mouse tracheal; rhesus bronchial), and ex vivo microdissected airways (rhesus and mouse) by measuring gene expression, glutathione content, and naphthalene metabolism. Glutathione levels and detoxification gene transcripts were measured after 1-hour exposure to 80 µM naphthalene (a bioactivated toxicant) or reactive naphthoquinone metabolites. Glutathione and glutathione-related enzyme transcript levels were maintained in ALI cultures from all species relative to source tissues, while cytochrome P450 monooxygenase gene expression declined. Notable species differences among the models included: a 40-fold lower total glutathione content for mouse ALI trachea cells relative to human and rhesus; a higher rate of naphthalene metabolism in mouse ALI cultures for naphthalene-glutathione formation (100-fold over rhesus) and naphthalene-dihydrodiol production (10-fold over human); and opposite effects of 1,2-naphthoquinone exposure in some models - glutathione was depleted in rhesus tissue but rose in mouse ALI samples. The responses of an immortalized bronchial cell line to naphthalene and naphthoquinones were inconsistent with those of human ALI cultures. These findings of preserved species differences and the altered balance of Phase-I and Phase-II xenobiotic metabolism among the characterized in vitro models should be considered for future pulmonary toxicity testing. [Description provided by NIOSH]
• Subjects:
  Animals Cells, Cultured Energy Metabolism Enzymes Genetics Hazardous Substances Laboratories Lung Naphthalenes Occupational Health Respiratory System Safety

  More +
• Keywords:
  Author Keywords: In Vitro Models; Naphthalene; Pulmonary Toxicity; Species Differences; Xenobiotic Metabolism In Vitro Study; Models; Animals; Laboratory Animals; Humans; Xenobiotics; Metabolism; Naphthalenes; Toxins; Lung; Enzymes; Cell Cultures; Detoxification; Genes; Metabolites; Sampling;
• ISSN:
  1040-0605
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Arizona ; California ; OSHA Region 9
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  323
• Issue:
  3
• NIOSHTIC Number:
  nn:20065629
• Citation:
  Am J Physiol Lung Cell Mol Physiol 2022 Sep; 323(3):L308-L328
• Contact Point Address:
  Laura S. Van Winkle, Department of Anatomy, Physiology & Cell Biology, Center for Comparative Respiratory Biology & Medicine, School of Veterinary Medicine/Center for Health & the Environment, University of California at Davis, Davis, CA, United States
• Email:
  lsvanwinkle@ucdavis.edu
• CAS Registry Number:
  Glutathione (CAS RN 70-18-8) ; Naphthalene (CAS RN 91-20-3)
• Federal Fiscal Year:
  2022
• Performing Organization:
  University of California - Davis
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  American Journal of Physiology: Lung Cellular and Molecular Physiology
• End Date:
  20270929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1ab202e81cc738940f93e8e0b883393bdc6ff3b01906c00e7a12565717b9ff402319a59135eabf8594968ff4a60503a25e94006f3d843b7a445bfd48c92fe5cd
• Download URL:
  https://stacks.cdc.gov/view/cdc/249495/cdc_249495_DS1.pdf
• File Type:
  [PDF - 5.54 MB ]