Differential effects of dihalogenated and trihalogenated acetates in the liver of B6C3F1 mice.
Haloacetates are produced in the chlorination of drinking water in the range 10--100 microg l(-1). As bromide concentrations increase, brominated haloacetates such as bromodichloroacetate (BDCA), bromochloroacetate (BCA) and dibromoacetate (DBA) appear at higher concentrations than the chlorinated haloacetates: dichloroacetate (DCA) or trichloroacetate (TCA). Both DCA and TCA differ in their hepatic effects; TCA produces peroxisome proliferation as measured by increases in cyanide-insensitive acyl CoA oxidase activity, whereas DCA increases glycogen concentrations. In order to determine whether the brominated haloacetates DBA, BCA and BDCA resemble DCA or TCA more closely, mice were administered DBA, BCA and BDCA in the drinking water at concentrations of 0.2--3 g l(-1). Both BCA and DBA caused liver glycogen accumulation to a similar degree as DCA (12 weeks). The accumulation of glycogen occurred in cells scattered throughout the acinus in a pattern very similar to that observed in control mice. In contrast, TCA and low concentrations of BDCA (0.3 g l(-1)) reduced liver glycogen content, especially in the central lobular region. The high concentration of BDCA (3 g l(-1)) produced a pattern of glycogen distribution similar to that in DCA-treated and control mice. This effect with a high concentration of BDCA may be attributable to the metabolism of BDCA to DCA. All dihaloacetates reduced serum insulin levels. Conversely, trihaloacetates had no significant effects on serum insulin levels. Dibromoacetate was the only brominated haloacetate that consistently increased acyl-CoA oxidase activity and rates of cell replication in the liver. These results further distinguish the effects of the dihaloacetates from those of peroxisome proliferators like TCA.
Kato-Weinstein
J
J
Pharmacology/Toxicology Program, College of Pharmacy, Washington State University, Pullman, WA 99164-6510, USA.
Stauber
A J
AJ
Orner
G A
GA
Thrall
B D
BD
Bull
R J
RJ
D000085:Acetates / Q000009:adverse effects*; D042962:Acyl-CoA Oxidase; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004202:Disinfectants; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006219:Halogens / Q000009:adverse effects*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D020675:Peroxisomes; D014018:Tissue Distribution; D014881:Water Supply
D000085:Acetates; D004202:Disinfectants; D006219:Halogens; D007328:Insulin; D006003:Glycogen; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D005947:Glucose