Abstract
It has been shown that oral anticarcinogen antibodies can decrease intestinal absorption of procarcinogens. So far, no attempts have been made to understand the potential modulatory effect of such antibodies on metabolic activation at mucosal surfaces. Moreover, the influence of naturally induced serosal-specific antibodies on absorptive transport of carcinogens remains unknown. In this study, the prototype food carcinogen benzo[a]pyrene (B[a]P) and a specific monoclonal antibody were used to address these questions in a bicompartmental model of polarized intestinal cells (Caco-2). Apical (i.e., luminal) administration of a 30-fold molar excess antibodies increased about 25-fold recovery of unmetabolized B[a]P, concomitantly with a decrease of 80% in both absorptive transport and formation of phenol metabolites. Interestingly, when metabolism was slowed down by antibodies, cross-reactive antibodies also increased at least 5-fold the extracellular levels of the 7,8-diol-B[a]P, interrupting subsequent activation steps. On the other hand, basolateral antibodies changed by 8-fold the rate of carcinogen appearance in the basolateral compartment, albeit without interfering with the apical cellular uptake or sequestration of either B[a]P or 7,8-diol-B[a]P by apical antibodies. Furthermore, basolateral antibodies reduced exposure of Caco-2 monolayers to B[a]P as demonstrated by a 50% decrease in apical efflux of 3-OH-B[a]P. These data show for the first time that both luminal and serosal antibodies may reduce the carcinogenic process by preventing high local concentrations, which would overload DNA repair mechanisms. This study also sheds light on the relevance of both naturally induced and immunoprophylactic antibodies against polycyclic aromatic hydrocarbon carcinogens.
Footnotes
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This research was supported by Fonds National de la Recherche Grant FNR/01/04/11 and the Centre de Recherche Public-Santé, Luxembourg. S.D.B. was supported by a fellowship of the Ministère de la Recherche, Luxembourg.
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doi:10.1124/jpet.104.081034.
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ABBREVIATIONS: GI, gastrointestinal; B[a]P, benzo[a]pyrene; PAH, polycyclic aromatic hydrocarbon; BPDE, 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; mAb, monoclonal antibody; HPLC, high-performance liquid chromatography; 7,8-diol-B[a]P, 7,8-dihydroxy-7,8-dihydrobenzo[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; TEER, transepithelial electrical resistance; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; P450, cytochrome P450; BL, basolateral.
- Received November 18, 2004.
- Accepted January 20, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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