Chemopreventive properties of chlorophyllin: inhibition of aflatoxin B1 (AFB1)-DNA binding in vivo and anti-mutagenic activity against AFB1 and two heterocyclic amines in the Salmonella mutagenicity assay.
Chlorophyllin (CHL), a sodium/copper derivative of chlorophyll, has been used to treat a number of human conditions with no toxic effects being reported. Recent studies have described the anti-mutagenic activity of CHL in several short-term genotoxicity assays; however, this compound has not been reported to inhibit carcinogen--DNA binding in vivo, and it has yet to be evaluated as an anti-carcinogen in any species. The chemopreventive properties of CHL were studied in trout using inhibition of aflatoxin B1 (AFB1)--DNA binding as an end-point. Chlorophyllin and AFB1 were coadministered in the diet, and carcinogen--DNA binding levels were determined in liver after 1, 3, 5 and 7 days. Linear increases in AFB1--DNA binding occurred with time of treatment at each CHL dose level (0, 500, 1000 and 2000 p.p.m.). Each increase in CHL dose produced a concomitant decrease in AFB1--DNA binding, resulting in a series of curves of decreasing slope. At the highest CHL dose level of 2000 p.p.m., AFB1--DNA binding was inhibited by 70%. These results suggest that CHL should be a potent inhibitor of AFB1-induced hepatocarcinogenesis in this model. In the Salmonella assay, CHL exhibited potent anti-mutagenic activity against AFB1 and two heterocyclic amines when incubated in the presence of trout liver activation systems. CHL also inhibited the mutagenic activity of AFB1-8,9-epoxide in the absence of a metabolic activation system. Dietary CHL substantially inhibited liver AFB1-DNA binding in vivo, even when AFB1 was given by i.p. injection to avoid direct AFB1--CHL interaction in the diet or gut. Collectively, these studies support a CHL inhibitory mechanism involving complex formation with the carcinogen in the gut coupled with electrophile scavenging or further complexing in the target organ.
Dashwood
R H
RH
Department of Environmental Biochemistry, University of Hawaii, Honolulu 96822.
Breinholt
V
V
Bailey
G S
GS
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002243:Carbolines / Q000633:toxicity*; D002735:Chlorophyllides / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000235:genetics*; D014337:Trout
D000348:Aflatoxins; D002243:Carbolines; D002735:Chlorophyllides; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D004247:DNA; D016604:Aflatoxin B1; C007020:chlorophyllin