Colonic cell proliferation, apoptosis and aberrant crypt foci development in rats given 2-amino-3-methylimidaz.
Sodium-copper chlorophyllin (CHL) inhibits the formation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colonic aberrant crypt foci (ACF) and tumours in the F344 rat when it is given simultaneously with either carcinogen. However, CHL reportedly increased the incidence of dimethylhydrazine (DMH)-induced colon tumours in the same species when administered post-initiation. In the present study, rats were given IQ (130 mg/kg body weight, by oral gavages on alternating days) for 2 weeks, starting in experiment week 3, and one week after the final IQ dose rats received CHL treatment until the study was terminated at 16 weeks. Compared with animals given carcinogen alone, the mean number of IQ-induced ACF per colon was reduced significantly by 1% (w/v) CHL in the drinking water (P < 0.05), whereas 0.1% and 0.01% CHL had no effect. These CHL concentrations increased in a dose-related manner both the terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) and bromodeoxyuridine (BrdU) labelling indices in the distal colon. However, the lowest concentration tested, 0.001% CHL, increased the mean number of IQ-induced ACF per colon (P < 0.05), and increased the BrdU labelling index without a concomitant change in TUNEL. These studies indicated that 0.001% CHL promoted IQ-ACF due to deregulation of the homeostatic balance between cell birth and apoptosis in the colonic mucosa, whereas higher concentrations of CHL had either no effect or protected against IQ-induced ACF by causing dose-related increases in the overall rate of cell turnover in the colon.
Dashwood
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Linus Pauling Institute, Oregon State University, Corvallis 97331-6512, USA. Rod.Dashwood@orst.edu
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Orner
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Horio
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D000284:Administration, Oral; D000818:Animals; D000963:Antimetabolites; D017209:Apoptosis; D001973:Bromodeoxyuridine; D002273:Carcinogens / Q000009:adverse effects*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D002735:Chlorophyllides / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D008297:Male; D009374:Neoplasms, Experimental; D011804:Quinolines / Q000009:adverse effects*; D051381:Rats; D011916:Rats, Inbred F344
D000963:Antimetabolites; D002273:Carcinogens; D002735:Chlorophyllides; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C007020:chlorophyllin; D001973:Bromodeoxyuridine