Down-regulation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in rats.
The inhibitory influence of bovine lactoferrin (bLF) on induction of preneoplastic hepatic glutathione S-transferase placental form-positive (GST-P( +)) cell foci and colon aberrant crypt foci (ACF) by diethylnitrosamine (DEN) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in F344 rats. Rats were initially treated with DEN, then placed on basal diet containing MeIQx (200 ppm) alone, MeIQx plus 2% bLF, or MeIQx plus 0.2% bLF from week 2 to week 8, with partial hepatectomy performed at week 3. Concomitant administration of 2% or 0.2% bLF with MeIQx caused significant dose-dependent decreases in both number and unit area of GST-P(+) cell foci (2% bLF, P < 0.001; 0.2% bLF, P < 0.01). Similar results were observed for MeIQx-induced colon ACF in the groups without DEN treatment (2% and 0.2% bLF, P < 0.05). To investigate the underlying mechanisms, we analyzed the influence of bLF on levels of cytochrome P4501A2 (CYP1A2), a metabolically activating enzyme of MeIQx in the liver. The results demonstrated that combined administration of 2% bLF significantly reduced levels of MeIQx-induced CYP1A2 mRNA (P < 0.05) and protein (P < 0.05) to the normal levels, in association with reduced values for MeIQx-DNA adducts (P < 0.05), liver GST-P(+) cell foci and colon ACF. These results suggest that bLF is a chemopreventive agent for DEN alone or DEN plus MeIQx-induced liver, and MeIQx-induced colon carcinogenesis in rats. One possible mechanism is a normalizing down-regulation of CYP1A2 expression by bLF, with consequent reduction of carcinogen activation and adduct formation.
Fujita
Ken-ichi
K
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045.
Ohnishi
Takamasa
T
Sekine
Kazunori
K
Iigo
Masaaki
M
Tsuda
Hiroyuki
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002273:Carcinogens; D002417:Cattle; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D018736:DNA Adducts; D004052:Diethylnitrosamine; D015536:Down-Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D007781:Lactoferrin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D016133:Polymerase Chain Reaction; D011804:Quinolines; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D011804:Quinolines; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D019388:Cytochrome P-450 CYP1A2; D005982:Glutathione Transferase; D007781:Lactoferrin; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline