Modulation of the metabolism and adverse effects of benzo[a]pyrene by a specific antibody: a novel host factor in environmental carcinogenesis?
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.
De Buck
Stefan S
SS
Institute of Immunology, Laboratoire National de Santé, Rue Auguste Lumière 20A, L-1011 Luxembourg, Luxembourg, Belgium.
Bouche
Fabienne B
FB
Brandenburger
Annick
A
Muller
Claude P
CP
D000478:Alkylation / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002273:Carcinogens / Q000009:adverse effects* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D002273:Carcinogens; D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1