Chlorophyllin (CHL), a water-soluble derivative of the green plant pigment,
chlorophyll, is an effective antimutagen and anticarcinogen in various model
systems when used as a modulator against a class of carcinogens that, in general,
have a structure consisting of at least three fused rings. Dibenzo[a,l]pyrene (DBP),
an extremely potent environmental carcinogen, has been isolated from urban air
samples, tobacco smoke, and coal smoke condensate. A study was conducted to
evaluate the complex interrelationships among dietary DBP doses with co-exposure
to a range of CHL doses. In order to achieve adequate statistical power in the
generation of multiple dose-response curves, this dose-dose matrix experiment
utilized over 12,000 rainbow trout. The resulting DNA adducts were assessed and
evaluated as biomarkers of exposure to discern their relationship with the final
tumor outcome.
CHL was highly effective in reducing DBP-initiated DNA adduct formation
in the liver and stomach and strongly inhibited tumor formation in the liver (56-79% inhibition), stomach (30-68%), and swim bladder (over 80% at the highest
DBP dose). Molecular dosimetry revealed adduct formation to be predictive of
final tumor response in both organs regardless of CHL dose. Other parameters
evaluated were consistent with CHL-mediated protection.
A clinical CHL preparation, evaluated in a human population subsequent to
the seminal demonstration of CHL chemopreventive properties against AFB��� in
trout (1), revealed CHL to be just as effective in reducing biomarkers of alfatoxin
exposure to humans (2). Dietary administration of this clinical preparation along
with DBP in the rainbow trout demonstrated CHL protective capacity against DBP-initiated
multi-organ DNA adduct formation and final tumor incidence.
Sucrose was evaluated, deemed unlikely to be sequestered in a complex
with CHL, and was used as a control in a pharmacokinetic study evaluating the
biodistribution of DBP with and without CHL. The results provide evidence against
a non-specific masking mechanism for CHL-mediated blocking of DBP (or
aflatoxin)-initiated tumorigenesis.
CHL at multiple doses provided significant protection against multi-dose
DBP-initiated DNA adduction and tumor formation in multiple organs. CHL-mediated
protection, primarily by reduced carcinogen biouptake and consistent
with a complexation mechanism, is supported by these results. / Graduation date: 2003
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/31143 |
| Date | 22 January 2003 |
| Creators | Pratt, Mary Margaret |
| Contributors | Bailey, George S. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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