title: Mode of action of butoxyethanol-induced mouse liver hemangiosarcomas and hepatocellular carcinomas.
abstract: Chronic exposure to 2-butoxyethanol resulted in an increase in liver hemangiosarcomas and hepatic carcinomas in male mouse liver. No increase in liver neoplasia was observed in similarly exposed male and female rats or female mice. We have proposed that the production of liver neoplasia in the male mouse is the result of oxidative damage secondary to the hemolytic deposition of iron in the liver. Our working hypothesis is that the mode of action of butoxyethanol-induced mouse liver hemangiosarcomas and hepatic neoplasia involves the metabolism of 2-butoxyethanol to butoxyacetic acid which results in the induction of RBC hemolysis. This hemolytic response is translated into the accumulation of iron in both liver hepatocytes and Kupffer cells. The Kupffer cell response to this insult is two-fold: (1) the production of oxidative species-through both Kupffer cell activation and through the Fenton reaction involving iron and (2) the production of cytokines (for example TNF alpha). The induction of reactive oxygen species can, if not scavenged, produce oxidative DNA damage (the formation of OH8dG), as well as increase cell growth through modulation of gene expression. While the reactive oxygen species generation would occur in the both rats and mice, the ability of the rat to detoxify the reactive oxygen species would preclude the remaining steps from occurring. In contrast, in the mouse, the reactive oxygen species would override antioxidant defense mechanisms and allow the proposed mode of action to move forward. Our results to date in male B6C3F1 mice and male F344 rats treated with 2-butoxyethanol (via daily gavage; five times per week) at doses of 0, 225, 450, and 900 mg/kg/day (mice) and 0, 225, 450 mg/kg/day (rats), respectively, showed: an increase in hemolysis in 2-butoxyethanol treated rats and mice in a dose-dependent manner, in addition, an increase in the percent of iron stained Kupffer cells in the liver was observed following treatment with 450 and 900 mg/kg of 2-butoxyethanol in mice and 225 and 450 mg/kg of 2-butoxyethanol in rat. With the iron deposition, a biphasic increase in oxidative damage (OH8dG and malondialdehyde) was seen in mouse liver after treatment with 2-butoxyethanol. In contrast, no increase in oxidative damage was observed in the rat liver at any of the doses examined. Concomitant with the increase in oxidative damage, Vitamin E levels were similarly reduced by 2-butoxyethanol in both mice and rat liver. However, the basal level of Vitamin E in rat liver was 2.5-fold greater than in mouse liver. A biphasic induction of DNA synthesis was seen following 2-butoxyethanol in the mouse. In mouse liver, increased DNA synthesis was observed in hepatocytes at 90 days and in endothelial cells at 7 and 14 days at all doses. No change in DNA synthesis was seen in 2-butoxyethanol treated rat liver. No apparent differences in apoptosis and mitosis in the liver were observed in mouse and rat liver between 2-butoxyethanol treatment groups and untreated controls. These results suggest that the induction of DNA synthesis, possibly from oxidative stress and/or Kupffer cell activation, occurs selectively in the mouse liver, in endothelial cells and in hepatocytes following exposure to 2-butoxyethanol, and support the hypothesis proposed above.
authors.affiliation: Indiana School of Medicine, 635 Barnhill Drive, MS 547, Indianapolis, IN 46202, USA. jklaunig@iupui.edu
authors.forename: J E
authors.initials: JE
authors.lastname: Klaunig
authors.forename: L M
authors.initials: LM
authors.lastname: Kamendulis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000633:toxicity*; D006394:Hemangiosarcoma / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006486:Hemosiderosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D007501:Iron / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D012997:Solvents / Q000633:toxicity*; D013045:Species Specificity
chemical_list: D005026:Ethylene Glycols; D016877:Oxidants; D017382:Reactive Oxygen Species; D012997:Solvents; D007501:Iron; C017096:n-butoxyethanol