title: Lack of effect of furfural on unscheduled DNA synthesis in the in vivo rat and mouse hepatocyte DNA repair assays and in precision-cut human liver slices.
abstract: The ability of furfural to induce unscheduled DNA synthesis (UDS) in hepatocytes of male and female B6C3F(1) mice and male F344 rats after in vivo administration and in vitro in precision-cut human liver slices has been studied. Preliminary toxicity studies established the maximum tolerated dose (MTD) of furfural to be 320 and 50 mg/kg in the mouse and rat, respectively. Furfural was dosed by gavage at levels of 0 (control), 50, 175 and 320 mg/kg to male and female mice and 0, 5, 16.7 and 50 mg/kg to male rats. Hepatocytes were isolated by liver perfusion either 2-4 h or 12-16 h after treatment, cultured in medium containing [3H]thymidine for 4 h and assessed for UDS by grain counting of autoradiographs. Furfural treatment did not produce any statistically significant increase or any dose-related effects on UDS in mouse and rat hepatocytes either 2-4 h or 12-16 h after dosing. In contrast, UDS was markedly induced in mice and rats 2-4 h after treatment with 20 mg/kg dimethylnitrosamine and 12-16 h after treatment of mice and rats with 200 mg/kg o-aminoazotoluene and 50 mg/kg 2-acetylaminofluorene (2-AAF), respectively. Precision-cut human liver slices from four donors were cultured for 24 h in medium containing [3H]thymidine and 0-10 mM furfural. Small increases in the net grain count (i.e. nuclear grain count less mean cytoplasmic grain count) observed with 2-10 mM furfural were not due to any increase in the nuclear grain count. Rather, it was the result of concentration-dependent decreases in the mean cytoplasmic grain counts and to a lesser extent in nuclear grain counts, due to furfural-induced cytotoxicity. In contrast, marked increases in UDS (both net grain and nuclear grain counts) were observed in human liver slices treated with 0.02 and 0.05 mM 2-AAF, 0.002 and 0.02 mM aflatoxin B(1) and 0.005 and 0.05 mM 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. This study demonstrates that furfural does not induce UDS in the hepatocytes of male and female B6C3F(1) mice and male F344 rats after oral treatment at doses up to the MTDs. Moreover, human liver slice studies suggest that furfural is also not a genotoxic agent in human liver.
authors.affiliation: TNO BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK. blake@tnobibra.co.uk
authors.forename: B G
authors.initials: BG
authors.lastname: Lake
authors.forename: A J
authors.initials: AJ
authors.lastname: Edwards
authors.forename: R J
authors.initials: RJ
authors.lastname: Price
authors.forename: B J
authors.initials: BJ
authors.lastname: Phillips
authors.forename: A B
authors.initials: AB
authors.lastname: Renwick
authors.forename: J A
authors.initials: JA
authors.lastname: Beamand
authors.forename: T B
authors.initials: TB
authors.lastname: Adams
mesh_terms: D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000494:pharmacology; D005260:Female; D005662:Furaldehyde / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344; D009762:o-Aminoazotoluene / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D004247:DNA; D015073:2-Acetylaminofluorene; D005662:Furaldehyde; D004128:Dimethylnitrosamine; D009762:o-Aminoazotoluene