Mechanisms of chlorophyllin anticarcinogenesis: dose-responsive inhibition of aflatoxin uptake and biodistribution following oral co-administration in rainbow trout.
Chlorophyllin (CHL) is a potent blocking agent against aflatoxin B(1) DNA adduction and tumorigenesis in the trout model, but mechanisms responsible for this chemoprotection in vivo are not well established. This study employed aflatoxin B(2) (AFB(2)), a structural analogue of AFB(1) that cannot be metabolized directly to the 8,9-exo-epoxide electrophile, to investigate CHL effects on carcinogen uptake and distribution kinetics following oral exposure in trout. CHL was shown to form an AFB(2) complex in vitro with a dissociation constant (K(d) = 1.92 +/- 0.13 microM) comparable to that with AFB(1). Following gavage, [(3)H]AFB(2) equivalents distributed rapidly from the stomach to other organs including blood, liver, and eventually to bile as a major repository. Bile was found to contain almost entirely parent AFB(2) 1 h after gavage, with a single metabolite dominating 3-24 h and an additional metabolite prominent by 48 h after gavage. Addition of sufficient CHL (>/=13.9 mM) to assure >99% complexation of AFB(2) (0.906 microM) in the gavage mix resulted in 80-90% reduction in AFB(2) equivalents in liver and bile 3 h after gavage. In three separate kinetic studies of up to 120 h postgavage, addition of >/=13.9 mM CHL to the gavage mix reproducibly and markedly delayed the rate of AFB(2) loss from stomach, retarded its appearance in blood, liver, and bile, and reduced peak AFB(2) concentrations in those tissues by up to 60%. Introduction of a food bolus immediately after gavage prolonged AFB(2) residence in stomach and intestine but did not abrogate the inhibitory effects of CHL on AFB(2) uptake and distribution. These results demonstrate that oral co-treatment with CHL under conditions where complex formation is initially assured, substantially reduces AFB(2) systemic uptake and target organ bioavailability in the trout.
Department of Food Science and Technology, Tokyo University of Fisheries, Tokyo, 108-8477, Japan.
T
T
Hayashi
M
M
Schimerlik
G
G
Bailey
D000348:Aflatoxins / Q000493:pharmacokinetics*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001646:Bile / Q000737:chemistry; D002735:Chlorophyllides / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005399:Fishes; D005766:Gastrointestinal Contents / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D013997:Time Factors; D014018:Tissue Distribution; D014337:Trout
D000348:Aflatoxins; D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D002735:Chlorophyllides; C007020:chlorophyllin