Journal Article

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

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

in Carcinogenesis

Volume 26, issue 4, pages 835-844
Published in print April 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi010
Modulation of the metabolism and adverse effects of benzo[a]pyrene by a specific antibody: a novel host factor in environmental carcinogenesis?

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The influence of specific antibodies on molecular and cellular mechanisms of activation, detoxification and biological activity 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 has been 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 the antibody may reduce their effective concentration in susceptible target organs and therefore relieve overloaded DNA repair mechanisms 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: AhR, cytosolic arylhydrocarbon receptor; ANF, α-naphthoflavone; B[a]P, benzo[a]pyrene; BPDE, 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; 7,8-diol-B[a]P, 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene; 1-OH-B[a]P, 1-hydroxybenzo[a]pyrene; 3-OH-B[a]P, 3-hydroxybenzo[a]pyrene; 9-OH-B[a]P, 9-hydroxybenzo[a]pyrene; P450, human cytochrome P450; PAH, polycyclic aromatic hydrocarbons; PBMC, peripheral blood mononuclear cells; PHA, phytohemagglutinin; trans-anti-B[a]P-tetrol, r-7,t-8,t-9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene

Journal Article.  7353 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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