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

• Published in: Carcinogenesis (New York) 2005-04, Vol.26 (4), p.835-844
• Main Authors: De Buck, Stefan S., Bouche, Fabienne B., Brandenburger, Annick, Muller, Claude P.
• Format: Article
• Language: English
• Subjects: 1-hydroxybenzo[a]pyrene; 1-OH-B[a]P; 10-epoxy-7; 10-tetrahydrobenzo[a]pyrene; 3-hydroxybenzo[a]pyrene; 3-OH-B[a]P; 8-dihydro-7; 8-dihydroxy-9; 8-dihydroxybenzo[a]pyrene; 8-diol-B[a]P; 9-hydroxybenzo[a]pyrene; 9-OH-B[a]P; AhR; Alkylation - drug effects; ANF; Animals; Antibodies, Monoclonal - pharmacology; B[a]P; Benzo(a)pyrene - metabolism; benzo[a]pyrene; Biological and medical sciences; BPDE; c-10-tetrahydroxy-7; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - adverse effects; Carcinogens - metabolism; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Proliferation - drug effects; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - immunology; Cytochrome P-450 CYP1A1 - metabolism; cytosolic arylhydrocarbon receptor; Dihydroxydihydrobenzopyrenes - adverse effects; Dihydroxydihydrobenzopyrenes - metabolism; DNA Adducts; Female; human cytochrome P450; Humans; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lymphocytes - drug effects; Medical sciences; Microsomes, Liver - drug effects; P450; PAH; PBMC; peripheral blood mononuclear cells; PHA; phytohemagglutinin; polycyclic aromatic hydrocarbons; r-7; Rats; Rats, Wistar; t-8; t-9; trans-anti-B[a]P-tetrol; Tumors; α-naphthoflavone
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi010

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.