Journal Article

Inhibition of dibenzo[<i>a</i>,<i>l</i>]pyrene-induced multi-organ carcinogenesis by dietary chlorophyllin in rainbow trout

Ashok P. Reddy, Ulrich Harttig, Marita C. Barth, William M. Baird, Michael Schimerlik, Jerry D. Hendricks and George S. Bailey

in Carcinogenesis

Volume 20, issue 10, pages 1919-1926
Published in print October 1999 | ISSN: 0143-3334
Published online October 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.10.1919
Inhibition of dibenzo[a,l]pyrene-induced multi-organ carcinogenesis by dietary chlorophyllin in rainbow trout

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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.

Keywords: AFB1, aflatoxin B1; BNF, β-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.

Journal Article.  7805 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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