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Carcinogenesis Advance Access published online on January 6, 2005
Carcinogenesis, doi:10.1093/carcin/bgi010
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Oxford University Press
Received October 27, 2004
Revised December 13, 2004
Accepted December 15, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Modulation of metabolism and adverse effects of benzo[a]pyrene by specific antibody: a novel host factor in environmental carcinogenesis?

Stefan S. De Buck 1, Fabienne B. Bouche 1, Annick Brandenburger 2, and Claude P. Muller 1*

1 Institute of Immunology, Laboratoire National de Santé, Rue Auguste Lumière 20A, L-1011 Luxembourg, Luxembourg
2 IRIBHM-IBMM, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, B-6041 Gosselies, Belgium

* To whom correspondence should be addressed.
Claude P. Muller, E-mail: claude.muller{at}LNS.ETAT.LU


  Abstract

The influence of specific antibodies on molecular and cellular mechanisms of activation, detoxification and biological activities of the ubiquitous carcinogen benzo[a]pyrene (B[a]P) was investigated using a monoclonal antibody. The antibody was shown to decrease cellular uptake and metabolic activation of B[a]P as demonstrated by higher recovery of unmetabolized B[a]P and decreased formation of end-point phenol metabolites in two types of target cells. Furthermore, strong antibody reactivity with 7,8-diol-B[a]P provided a second chance for interrupting metabolic activation by sequestration of this intermediate metabolite in the extracellular space. The biological relevance of B[a]P and 7,8-diol-B[a]P redistribution by antibody was demonstrated by reversion of B[a]P-induced inhibition of proliferation of human peripheral blood lymphocytes and by inhibition of CYP 1A1 induction in HepG2 cells. Remarkably, the antibody was still protective against B[a]P-induced immunotoxicity even after delayed addition, suggesting a more important role of metabolites in immunotoxicity than was appreciated so far. Although B[a]P is activated to 7,8-diol-B[a]P in the same cells that are inhibited by this metabolite, the antibody completely restored lymphocyte proliferation indicating that extracellular trapping of the 7,8-diol-B[a]P is biologically highly effective. Thus repartitioning of both B[a]P and its metabolites by antibody may reduce their effective concentration in susceptible target organs and therefore relieve overloaded DNA repair and inhibit carcinogen-induced P450 induction. These in vitro data also suggest that a natural or prophylactic antibody response against carcinogens may be associated with a reduced risk of cancer.

Keywords: Benzo[a]pyrene; Carcinogenesis; Antibody; Immunotoxicity; Cytochrome P450.
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