Discrimination of haptens from prohaptens using the metabolically deficient Cpr{sup low/low} mouse

Journal Article · Sun May 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.02.018· OSTI ID:21535283

Chipinda, Itai; Blachere, Francoise M; Anderson, Stacey E; Siegel, Paul D

The murine local lymph node assay (LLNA) is a validated, well accepted 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. This study was used to assess the utility of a pan microsomal metabolic deficient mouse to distinguish between direct acting haptens and prohaptens in the LLNA. Hapten and prohapten induced cell proliferation was compared in C57BL/6J (B6) wild type (WT) versus homozygous (HO) knockout mice with a hypomorphic NADPH-Cytochrome P450 Reductase (CPR) gene (termed Cpr{sup low/low}) resulting in low CPR enzyme activity. Mice were dosed with known prohaptens; benzo(a)pyrene (BaP), carvone oxime (COx) and paracetamol (PCM) and haptens; oxazolone (OX), 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (EtOX), and N-acetylbenzoquinoneimine (NABQI) in this study. Skin microsomes from the WT, HO and heterozygous (HT) Cpr{sup low/low} mice were compared and evaluated for CPR activity. Lymphocyte proliferative responses to BaP, COx and PCM were significantly abrogated by 36.4%, 45.2% and 50.8%, respectively; in Cpr{sup low/low} knock out (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{sup low/low} mice compared to the WT. Results of the present study suggest potential utility of the Cpr{sup low/low} mice in the LLNA to differentiate prohaptens from direct acting haptens.

• OSTI ID: 21535283
• Journal Information: Toxicology and Applied Pharmacology, Vol. 252, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.02.018; PII: S0041-008X(11)00072-X; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL PROLIFERATION
ENZYME ACTIVITY
GENES
LYMPH NODES
LYMPHOCYTES
METABOLIC ACTIVATION
MICE
MICROSOMES
SKIN
ANIMAL CELLS
ANIMALS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
CELL CONSTITUENTS
CONNECTIVE TISSUE CELLS
LEUKOCYTES
LYMPHATIC SYSTEM
MAMMALS
MATERIALS
METABOLISM
ORGANS
RIBOSOMES
RODENTS
SOMATIC CELLS
VERTEBRATES