title: Evaluation of serum and liver toxicokinetics for furan and liver DNA adduct formation in male Fischer 344 rats.
abstract: Furan is a food processing contaminant found in many common cooked foods that induces liver toxicity and liver cancer in animal models treated with sufficient doses. The metabolism of furan occurs primarily in the liver where CYP 2E1 produces a highly reactive bis-electrophile, cis-2-butene-1,4-dial (BDA). BDA reacts with nucleophilic groups in amino acids and DNA in vitro to form covalent adducts. Evidence for BDA-nucleoside adduct formation in vivo is limited but important for assessing the carcinogenic hazard of dietary furan. This study used controlled dosing with furan in Fischer 344 rats to measure serum and liver toxicokinetics and the possible formation of BDA-nucleoside adducts in vivo. After gavage exposure, furan concentrations in the liver were consistently higher than those in whole blood (∼6-fold), which is consistent with portal vein delivery of a lipophilic compound into the liver. Formation of BDA-2'-deoxycytidine in furan-treated rat liver DNA was not observed using LC/MS/MS after single doses as high as 9.2 mg/kg bw or repeated dosing for up to 360 days above a consistent background level (1-2 adducts per 10(8) nucleotides). This absence of BDA-nucleoside adduct formation is consistent with the general lack of evidence for genotoxicity of furan in vivo.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Churchwell
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Scheri
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Von Tungeln
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gamboa da Costa
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: F A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: daniel.doerge@fda.hhs.gov.
authors.forename: D R
authors.initials: DR
authors.lastname: Doerge
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects*; D004249:DNA Damage; D005663:Furans / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011916:Rats, Inbred F344; D066007:Toxicokinetics
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D005663:Furans; C015977:malealdehyde; D004247:DNA
keywords: Furan; Hepatocarcinogen; Hepatotoxicity; Mass spectrometry; Pharmacokinetics