title: Genotoxic potential and in vitro tumour-promoting potential of 2-dodecylcyclobutanone and 2-tetradecylcyclobutanone, two radiolytic products of fatty acids.
abstract: The DNA-damaging and tumour-promoting effects of two 2-alkylcyclobutanones (2-ACBs), which are found in irradiated fat-containing foods, were investigated by use of the comet assay and in an azoxymethane (AOM)-induced colon-carcinogenesis study in rats, respectively. We conducted genotoxicity tests of 2-dodecylcyclobutanone (2-dDCB) and 2-tetradecylcyclobutanone (2-tDCB) according to the test guidelines for chemicals or drugs. In addition, a cell-transformation assay with Bhas 42 cells was performed to investigate their promoting potential in vitro. The Salmonella typhimurium mutagenicity assay (Ames test), conducted with five tester strains, revealed that neither 2-dDCB nor 2-tDCB possessed mutagenic activity. Moreover, both in the in vitro chromosomal aberration test on CHL/IU cells and the in vivo bone-marrow micronucleus test where mice were given 2-dDCB and 2-tDCB (orally, up to 2000 mg/kg bw/day), we did not detect any clastogenic effects. Furthermore, DNA strand-breaks were not detected in the in vitro comet assay with CHL/IU cells, and DNA adducts derived from 2-dDCB and 2-tDCB were not detected in the colon tissues of the mice used for the micronucleus tests, in rats from a repeated dose 90-day oral toxicity test (0.03% 2-tDCB in the diet), or in rats from the AOM-induced carcinogenesis study (0.025% 2-tDCB in the diet). An in vitro tumour-promotion assay with Bhas 42 cells revealed that the number of transformed foci increased significantly following treatment of cells in the stationary phase with 2-dDCB or 2-tDCB for 10 days. Our results indicate that neither 2-dDCB nor 2-tDCB were genotoxic chemicals. However, they exhibited promoting activity, at least in vitro, when Bhas 42 cells were continuously exposed to these chemicals at toxic doses.
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan. Electronic address: yamakage.k@fdsc.or.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Yamakage
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sui
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ohta
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Toyoizumi
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Ikezumi
authors.affiliation: Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Negishi
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.affiliation: Food Safety Division, National Food Research Institute, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Todoriki
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Kondo
authors.initials: K
authors.lastname: Takashi
authors.affiliation: Laboratory of Quantum-Beam Chemistry and Biology, Radiation Research Center, Osaka Prefecture University, 1-2 Gakuen-cho, Sakai, Osaka 599-8570, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Furuta
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D002869:Chromosome Aberrations / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000473:pathology; D020552:Comet Assay; D006224:Cricetinae; D003503:Cyclobutanes / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry*; D005260:Female; D005514:Food Irradiation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects
chemical_list: D002273:Carcinogens; D003503:Cyclobutanes; D005227:Fatty Acids; D009153:Mutagens; C485436:2-tetradecylcyclobutanone; C063381:2-dodecylcyclobutanone; D001397:Azoxymethane
keywords: 2-Dodecylcyclobutanone; 2-Tetradecylcyclobutanone; Bhas 42 cell-transformation assay; Genotoxicity; Radiolytic products; Tumour-promoting effect