Carcinogenesis Advance Access published online on February 8, 2007
Carcinogenesis, doi:10.1093/carcin/bgm027
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Natural chlorophyll inhibits aflatoxin B1 induced multi-organ carcinogenesis in the rat
1 Linus Pauling Institute
2 Environmental and Molecular Toxicology Department
3 Department of Statistics, Oregon State University, Corvallis, OR 97331, USA
4 Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
5 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA
6 To whom correspondence should be addressed: Email: george.bailey{at}oregonstate.edu
Chemoprevention by chlorophyll (Chl) was investigated in a rat multi-organ carcinogenesis model. Twenty-one male F344 rats in 3 gavage groups (N = 7 rats each) received 5 daily doses of 250 µg/kg [3H]-AFB1 alone, or with 250 mg/kg chlrophyllin (CHL), or an equimolar amount (300 mg/kg) of Chl. CHL and Chl reduced hepatic DNA adduction by 42% (P = 0.031) and 55% (P = 0.008), respectively, AFB1-albumin adducts by 65% (P < 0.001) and 71% (P < 0.001), respectively, and the major AFB-N7-guanine urinary adduct by 90% (P = 0.0047) and 92% (P = 0.0029), respectively. To explore mechanisms, fluorescence quenching experiments established formation of a non-covalent complex in vitro between AFB1 and Chl (Kd = 1.22 ± 0.05 µM, stoichiometry = 1Chl : 1AFB1) as well as CHL (Kd = 3.05 ± 0.04 µM; stoichiometry = 1CHL : 1AFB1). The feces of CHL and Chl co-gavaged rats contained 137% (P = 0.0003) and 412% (P = 0.0048) more AFB1 equivalents, respectively, than control feces, indicating CHL and Chl inhibited AFB1 uptake. However, CHL or Chl treatment in vivo did not induce hepatic quinone reductase (NQO) or glutathione S-transferase (GST) above control levels. These results are consistent with a mechanism involving complex-mediated reduction of carcinogen uptake, and do not support a role for phase II enzyme induction in vivo under these conditions. In a second study, 30 rats in 3 experimental groups were dosed as in study 1, but for 10 days. At 18 weeks, CHL and Chl had reduced the volume % of liver occupied by GST-placental form positive foci by 74% (P < 0.001) and 77% (P < 0.001), respectively compared to control livers. CHL and Chl reduced the mean number of aberrant crypt foci per colon by 63% (P = 0.0026) and 75% (P = 0.0004), respectively. These results show Chl and CHL provide potent chemoprotection against early biochemical and late pathophysiological biomarkers of AFB1 carcinogenesis in the rat liver and colon
Received July 31, 2006; revised January 4, 2007; accepted January 29, 2007.
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