title: Chemical structure-related mechanisms underlying in vivo genotoxicity induced by nitrofurantoin and its constituent moieties in gpt delta rats.
abstract: Nitrofurans are antimicrobial compounds containing a nitro group at the 5-position of the furan ring and an amine or hydrazide side chain derivative. One member of the nitrofurans, nitrofurantoin (NFT), is a renal carcinogen in male rats despite its still controversial genotoxicity. We investigated chemical structure-related modes of action of NFT, and reporter gene mutation assays for NFT and its constituent moieties were performed. NFT, 5-nitro-2-furaldehyde (NFA), or 1-aminohydantoin (AHD) was administered to male F344 gpt delta rats by gavage for 4 or 13 weeks at a carcinogenic or the maximum tolerated dose. NFT caused a significant increase in gpt mutant frequency (MF) at 13 weeks with G-base substitution mutations. An increase in gpt MF was also observed in the NFA-treated group at 13 weeks, but not in the AHD-treated group. 8-Hydroxydeoxyguanosine (8-OHdG) levels in the kidney DNA of NFT-treated rats were significantly increased after 4 weeks. NFT caused accumulation of hyaline droplets indicated by positive immunostaining and western blot analysis for α2u-globulin in the proximal tubules. An additional study, in which female gpt delta rats were given NFT at the same dose used for males, was performed to mitigate the effect of α2u-globulin. NFT exerted the same effects on female rat kidneys to the same extent as males in terms of gpt MF and 8-OHdG level. Thus, it is highly probable that the structure of the nitro furan plays a key role in NFT-induced genotoxicity and genotoxic mechanisms including oxidative DNA damage are involved in NFT-induced renal carcinogenesis. α2u-globulin-mediated nephropathy may be a prerequisite for NFT-induced renal carcinogenesis in male rats, and additionally NFT could be a latent carcinogen in female rats and other animal species.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Kijima
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hibi
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Biological Safety Research Center, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan. Electronic address: umemura@nihs.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000510:Alpha-Globulins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins / Q000235:genetics*; D005260:Female; D005662:Furaldehyde / Q000031:analogs & derivatives / Q000633:toxicity; D006827:Hydantoins / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D009154:Mutation; D009582:Nitrofurantoin / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010430:Pentosyltransferases / Q000235:genetics*; D011916:Rats, Inbred F344; D018570:Risk Assessment; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C504350:1-aminohydantoin; D000510:Alpha-Globulins; D015415:Biomarkers; D029968:Escherichia coli Proteins; D006827:Hydantoins; D009153:Mutagens; C013803:alpha 2u globulin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D009582:Nitrofurantoin; D005662:Furaldehyde; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; D003849:Deoxyguanosine; C052590:5-nitro-2-furaldehyde
keywords: In vivo mutagenicity; Kidney; Nitrofurantoin; gpt delta rat