Differentiation of prohaptens from direct acting contact chemical allergens using a cytochrome p450 reductase deficient mouse model

Details

• Personal Author:
  Anderson, Stacey E. ; Blachere, Francoise M. ; Chipinda I ; Siegel, Paul D.
• Description:
  The murine local lymph node assay (LLNA) is a well accepted, validated method for identification of chemical contact allergens. Both direct acting haptens and prohaptens (requiring metabolic activation) can be identified, but not differentiated by this assay. The objective of this study was to assess the utility of a pan microsomal metabolic deficient mouse (CPR low/low) to distinguish between direct acting haptens and prohaptens in the LLNA. LLNA cell proliferation was compared in C57BL/6J (B6) wild type vs. homozygous CPR low/low mouse, congenic with the B6 strain, having a hypomorphic NADPH-cytochrome P450 reductase (CPR) gene resulting in low microsomal enzyme activity. The known prohaptens, benzo(a)pyrene (BaP), carvone oxime (CVO) and paracetamol (PCM) and direct binding haptens, oxazolone (OX), 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (EtOX), and N-acetylbenzoquinoneimine (NABQI) employed in the present study. Skin microsomes from the wild type (WT) and CPR low/low homozygous (HM) and heterozygous (HT) knock-out (KO) mice were assayed and compared for CPR activity. Lymphocyte proliferative responses to BaP, CVO and PCM were significantly abrogated by 36.4%, 45.2% and 50.8%, respectively; in CPR low/low KO mice versus WT mice; while the lymphocyte proliferative responses to the direct acting haptens OX, EtOX and NABQI were comparable. CPR activity, determined as Units/mg protein was determined to be significantly lower in the CPR low/low KO mice compared to the WT. Results of the present study suggest potential utility employing the LLNA in the CRP low/low mouse in conjunction with WT to differentiate pro- vs. direct acting haptens. [Description provided by NIOSH]
• Subjects:
  Cell Division Chemistry Cytotoxins Hazardous Substances Hypersensitivity Laboratories Microbiology Occupational Health Safety Skin
• Keywords:
  Biological-effects Cell-biology Cell-division Cellular-reactions Chemical-hypersensitivity Chemical-reactions Cytotoxic-effects Exposure-levels Laboratory-animals Laboratory-testing Microscopic-analysis Nanotechnology Physiological-effects Quantitative-analysis Skin-exposure Skin-irritants Statistical-analysis Toxic-effects

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  District of Columbia ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  17-18
• Volume:
  120
• NIOSHTIC Number:
  nn:20038438
• Citation:
  Toxicologist 2011 Mar; 120(Suppl 2):17-18
• CAS Registry Number:
  Benzo[a]pyrene (CAS RN 50-32-8)
• Federal Fiscal Year:
  2011
• NORA Priority Area:
  Services
• Peer Reviewed:
  False
• Supplement:
  2
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7a1e7375608eca1205d04a2778c959b25f62ca3c19230b5703a67bcbad23ade813e8364b76d26f5b103ef5d326142e2766c9a4d28adc82e8651fa9faf24834b8
• Download URL:
  https://stacks.cdc.gov/view/cdc/192151/cdc_192151_DS1.pdf
• File Type:
  [PDF - 1.11 MB ]