Evidence of oxidative stress and associated DNA damage, increased proliferative drive, and altered gene expression in rat liver produced by the cholangiocarcinogenic agent furan.
Furan is a potent cholangiocarcinogen in rat by an as yet undefined mechanism. The risk to man remains unclear. Using a time-course stop study design, we have investigated the potential of furan to induce oxidative stress and DNA damage associated with inflammatory and regenerative responses in rat liver. Furan was administered via oral gavage (30 mg/kg b.w. 5 daily doses per week), and livers were analyzed at time points between eight hr and three months. A one-month recovery group previously treated for three months was also included. There was a marked association between CYP2E1 expression and DNA oxidation (8-oxo-dG) in areas of centrilobular hepatocyte necrosis seen after a single dose. After one-month recovery from three-month treatment, 8-oxo-dG was still observed in areas of furan-induced cholangiofibrosis. Furan-induced changes in the expression of various genes associated with oxidative stress, DNA damage, and cell cycle control were identified during treatment and recovery. We propose that furan-induced cholangiocarcinomas emerge from areas of cholangiofibrosis as a result of a combination of chronic, persistent indirect damage to DNA through oxygen radicals coupled with persistent proliferative signals, including loss of connexin 32, that act to convert this DNA damage to fixed mutations.
Hickling
K C
KC
Safety Assessment, AstraZeneca R&D Charnwood, Loughborough, United Kingdom. Kevin.Hickling@Astrazeneca.com
Hitchcock
J M
JM
Oreffo
V
V
Mally
A
A
Hammond
T G
TG
Evans
J G
JG
Chipman
J K
JK
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008679:Metaplasia / Q000139:chemically induced / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats
D002273:Carcinogens; D005663:Furans; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019392:Cytochrome P-450 CYP2E1; D003849:Deoxyguanosine; C039281:furan