title: Effects of chlorophyllin on transport of dibenzo(a, l)pyrene, 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine, and aflatoxin B(1) across Caco-2 cell monolayers.
abstract: Chlorophyllin (CHL) is a sodium copper derivative of chlorophyll that is capable of forming strong non-covalent complexes with several known carcinogens. Antimutagenic and anticarcinogenic effects, including reduced DNA adduct and tumor formation have been demonstrated for CHL against aflatoxin B(1) (AFB(1)), dibenzo(a,l)pyrene (DBP) and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP). Alterations in uptake and/or metabolism of planar molecules with at least partial ring structure have been proposed as mechanisms of action for CHL chemoprevention. The Caco-2 cell model of intestinal epithelial transport was used to evaluate the absorption of 1 microM DBP, AFB(1) and PhIP across cell monolayers in the presence of 0, 1, 10, and 100 microM CHL. No significant differences were observed in the permeability (P(e)) of DBP and AFB(1) from the basolateral-to-apical (BL --> AP) compared to apical-to-basolateral (AP --> BL) compartments for DBP and AFB(1), however, the P(e) of PhIP from BL --> AP, 1.26 x 10(5) +/- 2.10 x 10(6) cm/s, was significantly higher than AP --> BL, 5.83 x 10(6) +/- 7.56 x 10(7) cm/s, (P<0.001) suggesting an active efflux pathway. Transport of DBP from AP --> BL compartments was significantly reduced at all CHL concentrations (P<0.05). AP --> BL transport of AFB(1) was significantly reduced by the addition of 100 microM CHL (P<0.05) while 1 microM or 10 microM CHL had no effect. Complexation studies revealed a higher binding affinity (K(b)) for DBP to CHL compared to AFB(1) to CHL in transport buffer. AP --> BL transport of PhIP, which has a lower binding affinity for CHL than AFB(1) or DBP, was not significantly altered by the addition of CHL. These data suggest that the transport of AFB(1) and DBP can be inhibited by CHL, which supports a model of direct binding in the intestinal tract of CHL to these carcinogens with resultant reduction of bioavailability as one mechanism of action as a cancer chemopreventive agent.
authors.affiliation: Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR 97331, USA. john.mata@oregonstate.edu
authors.forename: John E
authors.initials: JE
authors.lastname: Mata
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yu
authors.forename: John E
authors.initials: JE
authors.lastname: Gray
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Rosita
authors.initials: R
authors.lastname: Rodriguez-Proteau
mesh_terms: D016604:Aflatoxin B1 / Q000378:metabolism*; D000465:Algorithms; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001580:Benzopyrenes / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects; D002021:Buffers; D018938:Caco-2 Cells; D002273:Carcinogens / Q000494:pharmacology*; D002735:Chlorophyllides / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D009153:Mutagens / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D001580:Benzopyrenes; D002021:Buffers; D002273:Carcinogens; D002735:Chlorophyllides; D007093:Imidazoles; D009153:Mutagens; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D016604:Aflatoxin B1; C007020:chlorophyllin; C041517:dibenzo(a,l)pyrene