Title

Enhanced excretion of dietary carcinogen via antibody-mediated sequestration

Date of Completion

January 1999

Keywords

Health Sciences, Pharmacology|Biology, Animal Physiology|Health Sciences, Immunology|Health Sciences, Oncology

Degree

Ph.D.

Abstract

The ability to control the absorption of low-molecular weight (<500 D) compounds (LMWC's) across mucosal surfaces would be valuable for preventing disease. Most LMWC's, e.g. chemical carcinogens and drugs, are absorbed across mucosal epithelia that are normally protected by secretory antibodies which specifically bind to pathogens and prevent their adherence to the epithelium. Exposure to LMWC's does not evoke antibody secretion and LMWC absorption is usually unhindered. We hypothesized that passively-administered carcinogen-specific antibodies may reduce carcinogen absorption and that maximal binding site affinity would optimize chemical sequestration within the gastrointestinal lumen. Mice perorally administered a mixture of specific antibody and the model carcinogen 125I-N-2-(4-hydroxyphenyl-acetamido)fluorene (125I-pHP-AAF) excreted more total and antibody-bound radiotracer in feces than did controls. HPLC analysis indicated the majority of fecal radiotracer excreted from specific-antibody treated mice was unmetabolized 125I-pHP-AAF. Specific-antibody treated mice excreted 96% less radiotracer in urine indicating a reduction in gastrointestinal absorption of 125I-pHP-AAF. Thus, ingestion of specific antibodies decreased gastrointestinal absorption and increased fecal excretion of 125I-pHP-AAF. ^ Previous work suggested that binding site affinity might have greater significance than titer upon chemical sequestration within the gastrointestinal tract. To compare the contribution of binding site affinity versus titer on chemical sequestration, 3H-biotin pharmacodynamics, were compared between mice given combinations of avidin or activated charcoal and 3H-biotin. Mixing avidin and 3H-biotin before peroral administration reduced 3H-biotin absorption, as indicated by increased fecal 3H-biotin excretion and reduced 3H-biotin in urine and tissues compared to controls. 3H-biotin absorption in mice was also reduced when avidin was administered up to four hours prior to 3H-biotin or by giving a mixture of 3H-biotin and activated charcoal. However, activated charcoal administration prior to 3H-biotin did not prevent 3H-biotin absorption. Thus, high affinity protein binding sites may be used to prophylactically coat the gastrointestinal tract and prevent the subsequent absorption of a chemical ligand. Taken together, these studies suggest a novel mechanism for protection against environmental carcinogens. ^