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
article
The ability of furfural to induce unscheduled DNA synthesis (UDS) in hepatocytes of male and female B6C3F<sub>1</sub> 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 [<sup>3</sup>H]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 [<sup>3</sup>H]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<sub>1</sub> 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<sub>1</sub> 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. © 2001 Elsevier Science Ltd. All rights reserved.
Topics
FurfuralHuman liverIn vivo DNA repairMouse hepatocytesPrecision-cut liver slicesRat hepatocytesUnscheduled DNA synthesis2 amino 1 methyl 6 phenylimidazo[4,5 b]pyridineAflatoxin B1AminoazotolueneDimethylnitrosamineFurfuralN (2 fluorenyl)acetamideThymidineAnimal cellAnimal experimentAnimal modelAnimal tissueAssayAutoradiographyControlled studyCytotoxicityDNA repairDose responseFemaleGenotoxicityHumanHuman cellHuman tissueLiver cellLiver perfusionMaleMaximum tolerated doseMouseNonhumanRatUnscheduled DNA synthesis2-AcetylaminofluoreneAnimalsCarcinogensCells, CulturedDimethylnitrosamineDNADNA RepairDNA ReplicationFemaleFuraldehydeHepatocytesHumansLiverMaleMiceMice, Inbred Strainso-AminoazotolueneRatsRats, Inbred F344
TNO Identifier
87593
Source
Food and Chemical Toxicology, 39, pp. 999-1011.
Pages
999-1011
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