TY - JOUR
T1 - Modulation of the metabolism and adverse effects of benzo[a]pyrene by a specific antibody
T2 - A novel host factor in environmental carcinogenesis?
AU - De Buck, Stefan S.
AU - Bouche, Fabienne B.
AU - Brandenburger, Annick
AU - Muller, Claude P.
N1 - Funding Information:
The authors acknowledge the skilful assistance of the following staff members at the Laboratoire National de Santé, Dr Corinne Ensch for bioconjugation of benzo[a]pyrene and Wim Ammerlaan for expert advice and thoughtful suggestions concerning flow cytometry analysis. We thank Prof. Thierry Vélu (UniversitéLibre de Bruxelles) for fruitful discussions and guidance. This research was sponsored by Fonds National de la Recherche grant FNR/01/ 04/11 and Bourse BFR from the Ministère de la Recherche, Luxembourg and CRP-Santé, Luxembourg.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=17844398525&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgi010
DO - 10.1093/carcin/bgi010
M3 - Article
C2 - 15637092
AN - SCOPUS:17844398525
SN - 0143-3334
VL - 26
SP - 835
EP - 844
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -