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CYP1A2 is not required for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced immunosuppression

R J Smialowicz1, D E Burgin, W C Williams

  • 1Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. smialowicz.ralph@epa.gov

Toxicology
|March 9, 2004
PubMed

Insights

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure suppresses antibody responses in mice. CYP1A2 enzyme is not required for this TCDD-induced immunosuppression, as shown by studies comparing wild-type and knockout mice.

Area of Science:

  • Immunotoxicology
  • Environmental Toxicology
  • Pharmacogenetics

Background:

  • 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant.
  • Suppression of antibody response to sheep red blood cells (SRBCs) is a sensitive immunotoxic endpoint of TCDD exposure.
  • Hepatic cytochrome P450 enzymes, including CYP1A2, are involved in TCDD metabolism and sequestration.

Purpose of the Study:

  • To investigate the role of CYP1A2 in TCDD-induced immunosuppression.
  • To compare the effects of TCDD on antibody responses in wild-type, heterozygous, and knockout CYP1A2 mice.

Main Methods:

  • Groups of C57BL/6N mice (CYP1A2 +/+, +/-, and -/-) were administered single oral doses of TCDD.
  • Mice were immunized with SRBCs, and antibody titers were measured using ELISA.
  • Body, spleen, thymus, and liver weights were recorded.

Main Results:

  • TCDD suppressed anti-SRBC titers in all mouse strains.
  • CYP1A2 (-/-) mice exhibited a three-fold increase in immunosuppression sensitivity compared to wild-type mice.
  • Liver weight increases, observed in wild-type mice at higher TCDD doses, were absent in CYP1A2 (-/-) mice.

Conclusions:

  • CYP1A2 is not essential for TCDD-induced immunosuppression.
  • The inability of CYP1A2 (-/-) mice to sequester TCDD in the liver may lead to increased systemic exposure and heightened immunosuppression.

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