Carcinogenesis, Vol. 20, No. 10, 1919-1926,
October 1999
© 1999 Oxford University Press
Molecular Epidemiology and Cancer Prevention |
Inhibition of dibenzo[a,l]pyrene-induced multi-organ carcinogenesis by dietary chlorophyllin in rainbow trout
Department of Environmental and Molecular Toxicology and
1 Department of Biochemistry and Biophysics, Oregon State University, Corvallis,OR 97331, USA
Cancer chemoprevention by dietary chlorophyllin (CHL) was investigated in a rainbow trout multi-organ tumor model. In study 1, duplicate groups of 130 juvenile trout were treated for 2 weeks with control diet, 500 p.p.m. dibenzo[a,l]pyrene (DB[a,l]P) or 500 p.p.m. DB[a,l]P + 2052 p.p.m. CHL, then returned to control diet. DB[a,l]P alone proved somewhat toxic but induced high tumor incidences in liver (61%), stomach (91%) and swimbladder (53%) 11 months after initiation. CHL co-feeding abrogated DB[a,l]P acute toxicity and reduced tumor incidences to 18% in liver, 34% in stomach and 3% in swimbladder (P 
0.01). A second tumor and DNA adduct study using a non-toxic initiation protocol (200 p.p.m. DB[a,l]P ± 4000 p.p.m. CHL for 4 weeks) confirmed these results. Potential CHL inhibitory mechanisms were investigated. Dietary CHL inhibited hepatic DB[a,l]P–DNA adducts in the two tumor studies by 89 and 76%, respectively. CHL was shown to complex strongly with DB[a,l]P (Kd1,2 = 1.59 ± 0.01 µM, stoichiometry 2CHL:DB[a,l]P) and strongly inhibited DB[a,l]P mutagenesis in the Salmonella assay. Significant inhibition occurred at CHL concentrations substantially less than stoichiometric with DB[a,l]P and thus not reflecting simple DB[a,l]P sequestration via complexation. These initial findings suggest that CHL chemoprevention reflects complexation that might limit DB[a,l]P uptake in vivo, antimutagenic mechanisms such as catalytic degradation of the proximate electrophile in target cells, or both. These results demonstrate that dietary CHL is a reproducibly effective chemopreventive agent for DB[a,l]P multi-organ tumorigenesis in trout and suggest that reduced DB[a,l]P–DNA adducts may be predictive biomarkers of CHL reduction of DB[a,l]P-initiated hepatic tumors.
Abbreviations: AFB1, aflatoxin B1; BNF, ß-naphthoflavone; CHL, chlorophyllin; DB[a,l]P, dibenzo[a,l]pyrene; DMBA, 7,12-dimethylbenz[a]anthracene; DMSO, dimethylsulfoxide; DTE, dithioerythritol; OTD, Oregon test diet; PhIP, 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine; THF, tetrahydrofuran.
2 To whom correspondence should be addressed Email: george.bailey{at}orst.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. J. Castro, C. V. Lohr, K. A. Fischer, K. M. Waters, B.-J. M. Webb-Robertson, R. H. Dashwood, G. S. Bailey, and D. E. Williams Identifying efficacious approaches to chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a mouse model of transplacental carcinogenesis Carcinogenesis, February 1, 2009; 30(2): 315 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Simonich, P. A. Egner, B. D. Roebuck, G. A. Orner, C. Jubert, C. Pereira, J. D. Groopman, T. W. Kensler, R. H. Dashwood, D. E. Williams, et al. Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat Carcinogenesis, June 1, 2007; 28(6): 1294 - 1302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Margaret Pratt, A. P. Reddy, J. D. Hendricks, C. Pereira, T. W. Kensler, and G. S. Bailey The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between, dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers and final tumor outcome Carcinogenesis, March 1, 2007; 28(3): 611 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yu, C. V. Loehr, K. A. Fischer, M. A. Louderback, S. K. Krueger, R. H. Dashwood, N. I. Kerkvliet, C. B. Pereira, J. E. Jennings-Gee, S. T. Dance, et al. In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor Cancer Res., January 15, 2006; 66(2): 755 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Diaz, Q. Li, and R. H. Dashwood Caspase-8 and Apoptosis-inducing Factor Mediate a Cytochrome c-independent Pathway of Apoptosis in Human Colon Cancer Cells Induced by the Dietary Phytochemical Chlorophyllin Cancer Res., March 15, 2003; 63(6): 1254 - 1261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Williams, G. S. Bailey, A. Reddy, J. D. Hendricks, A. Oganesian, G. A. Orner, C. B. Pereira, and J. A. Swenberg The Rainbow Trout (Oncorhynchus mykiss) Tumor Model: Recent Applications in Low-Dose Exposures to Tumor Initiators and Promoters Toxicol Pathol, January 1, 2003; 31(1_suppl): 58 - 61. [Abstract] [PDF]
|
|