Dichloroacetate toxicokinetics and disruption of tyrosine catabolism in B6C3F1 mice: dose-response relationships and age as a modifying factor.
Dichloroacetate (DCA) is a rodent carcinogen commonly found in municipal drinking water supplies. Toxicokinetic studies have established that elimination of DCA is controlled by liver metabolism, which occurs by the cytosolic enzyme glutathione-S-transferase-zeta (GST-zeta). DCA is also a mechanism based inhibitor of GST-zeta, and a loss in GST-zeta enzyme activity occurs following repeated doses or prolonged drinking water exposures. GST-zeta is identical to an enzyme that is part of the tyrosine catabolism pathway known as maleylacetoacetate isomerase (MAAI). In this pathway, GST-zeta plays a critical role in catalyzing the isomerization of maleylacetoacetate to fumarylacetoacetate. Disruption of tyrosine catabolism has been linked to increased cancer risk in humans. We studied the elimination of i.v. doses of DCA to young (10 week) and aged (60 week) mice previously treated with DCA in their drinking water for 2 and 56 weeks, respectively. The diurnal change in blood concentrations of DCA was also monitored in mice exposed to three different drinking water concentrations of DCA (2.0, 0.5 and 0.05 g/l). Additional experiments measured the in vitro metabolism of DCA in liver homogenates prepared from treated mice given various recovery times following treatment. The MAAI activity was also measured in liver cytosol obtained from treated mice. Results indicated young mice were the most sensitive to changes in DCA elimination after drinking water treatment. The in vitro metabolism of DCA was decreased at all treatment rates. Partial restoration ( approximately 65% of controls) of DCA elimination capacity and hepatic GST-zeta activity occurred after 48 h recovery from 14 d 2.0 g/l DCA drinking water treatments. Recovery from treatments could be blocked by interruption of protein synthesis with actinomycin D. MAAI activity was reduced over 80% in liver cytosol from 10-week-old mice. However, MAAI was unaffected in 60-week-old mice. These results indicate that in young mice, inactivation and re-synthesis of GST-zeta is a highly dynamic process and that exogenous factors that deplete or reduce GST-zeta levels will decrease DCA elimination and may increase the carcinogenic potency of DCA. As mice age, the elimination capacity for DCA is less affected by reduced liver metabolism and mice appear to develop some toxicokinetic adaptation(s) to allow elimination of DCA at rates comparable to naive animals. Reduced MAAI activity alone is unlikely to be the carcinogenic mode of action for DCA and may in fact, only be important during the early stages of DCA exposure.
Schultz
I R
IR
Battelle Pacific Northwest National Laboratories, Richland, WA 99352, USA. ir_schultz@pnl.gov
Merdink
J L
JL
Gonzalez-Leon
A
A
Bull
R J
RJ
D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001835:Body Weight; D002940:Circadian Rhythm / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D005618:Fresh Water; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism*; D019745:cis-trans-Isomerases / Q000032:analysis
D014443:Tyrosine; D003999:Dichloroacetic Acid; D005982:Glutathione Transferase; D019745:cis-trans-Isomerases; C021531:maleylacetoacetate isomerase