Effects of 2-butoxyethanol on hepatic oxidative damage.
2-Butoxyethanol has been reported to induce an increase in liver tumors in male B6C3F1 mice following chronic inhalation while rats, similarly treated, showed no increase in liver tumors. The mechanism for the selective induction of cancer in mouse liver is unknown, however, 2-butoxyethanol has been shown to induce hemolysis in mice, resulting in an accumulation of hemosiderin (iron) in the liver. Previous studies by our group and others have shown that mouse liver compared to other rodent species has a lower antioxidant capacity and appears to be more susceptible to chemically-induced oxidative damage. Since iron is known to produce hydroxyl radicals (through the Fenton reaction), we have proposed that the 2-butoxyethanol-induced iron overload (through hemolysis) may contribute to the induction of liver neoplasia in the mouse. In the present studies, 2-butoxyethanol induced oxidative stress in the liver of mice following 7-day treatment by gavage. These studies also examined whether 2-butoxyethanol, 2-butoxy acetic acid (a major metabolite of 2-butoxyethanol) or iron (FeSO(4)) produced oxidative stress in mouse and rat hepatocytes. Oxidative stress was examined by measuring oxidative DNA damage (OH8dG), lipid peroxidation (MDA formation) and cellular vitamin E concentrations. Neither 2-butoxyethanol or 2-butoxyacetic acid induced changes in the oxidative stress parameters examined in either rat or mouse hepatocytes. In contrast, FeSO(4) produced a dose-related increase in OH8dG and MDA and a decrease in vitamin E levels following 24 h treatment. Mouse hepatocytes were more sensitive than rat hepatocytes to the oxidative damage induced by the FeSO(4). FeSO(4)-induced oxidative stress was not increased by co-treatment of FeSO(4) with either 2-butoxyethanol or 2-butoxy acetic acid. These results support the proposal that the induction of hepatic oxidative stress by 2-butoxyethanol in vivo occurs secondary to induction of hemolysis and iron deposition in the liver rather than as a direct action of 2-butoxyethanol or its main metabolite, 2-butoxy acetic acid.
Park
Joungjoa
J
Division of Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, MS 1021, Indianapolis, IN 46202, USA.
Kamendulis
Lisa M
LM
Klaunig
James E
JE
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D005026:Ethylene Glycols / Q000633:toxicity*; D005296:Ferrous Compounds / Q000494:pharmacology* / Q000633:toxicity; D006016:Glycolates / Q000633:toxicity*; D006461:Hemolysis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D014810:Vitamin E / Q000032:analysis
D005026:Ethylene Glycols; D005296:Ferrous Compounds; D006016:Glycolates; D014810:Vitamin E; C017095:n-butoxyacetic acid; C020748:ferrous sulfate; D008315:Malondialdehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D007770:L-Lactate Dehydrogenase; D003849:Deoxyguanosine; C017096:n-butoxyethanol