title: Relationship between CYP1A induction by indole-3-carbinol or flutamide and liver tumor-promoting potential in rats.
abstract: To investigate liver tumor-promoting potentials of indole-3-carbinol (I3C) and flutamide (FLU), changes in mRNA expression of Cyp1a and genes encoding antioxidant/detoxifying enzymes in the liver, 6-week-old male F344 rats were subjected to medium-term liver bioassay. β-Naphthoflavone (BNF), a strong CYP1A inducer, was also used for comparison. Two weeks after initiation with N-diethylnitrosamine (DEN), animals were fed a basal diet (untreated controls) or a diet containing 0.5% I3C, 0.1% FLU, or 0.5% BNF for 6 weeks. Each animal was subjected to a two-third partial hepatectomy 1 week after the start of promoter treatments. Histopathologically, I3C and BNF increased altered liver cell foci with the incidence (3.7- and 7.3-fold) and multiplicity (8.3- and 13.8-fold) compared with the DEN-alone group, respectively. Immunohistochemically, I3C significantly increased the number (3.1-fold; P < 0.01) and area (2.4-fold; P < 0.05) of foci positive for glutathione-S-transferase placental form (GST-P) compared with the DEN-alone group; FLU induced a slight but significant increase in the number of GST-P-positive foci (2.8-fold; P < 0.05) whereas BNF showed marked induction of the number and area of GST-P-positive foci (20- and 14-fold, respectively; P < 0.01). In parallel, I3C, FLU, and BNF markedly increased mRNA levels of Cyp1a1 (50-, 23-, 299-fold) and antioxidant/detoxifying enzymes such as Gpx2 and Nqo1 as shown by real-time reverse transcription-polymerase chain reaction analysis. These results suggest that I3C and FLU could promote hepatocellular tumors in parallel with that of CYP1A's potential to cause subsequent oxidative stress responses in rats.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Dewa
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kemmochi
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Masako
authors.initials: M
authors.lastname: Imaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity; D004790:Enzyme Induction; D005485:Flutamide / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006498:Hepatectomy; D007150:Immunohistochemistry; D007211:Indoles / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D007211:Indoles; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D019324:beta-Naphthoflavone; D005485:Flutamide; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat