Pharmacologic or genetic ablation of maleylacetoacetate isomerase increases levels of toxic tyrosine catabolites in rodents.
Dichloroacetate (DCA) is both an environmental contaminant and an investigational drug for diseases involving perturbed mitochondrial energetics. DCA is biotransformed to glyoxylate by maleylacetoacetate isomerase (MAAI). Previous studies have shown that DCA decreases MAAI activity in rat liver in a time- and dose-dependent manner and may target the protein for degradation in vivo. We now report that the MAAI protein is depleted in a time- and dose-dependent manner in the livers of Sprague-Dawley rats exposed to DCA. This decrease in protein expression is not mirrored by a decrease in the steady-state levels of MAAI mRNA, indicating that the depletion is exclusively a post-transcriptional event. We also investigated the pharmacokinetics of DCA in the recently developed MAAI knockout (MAAI-KO) mouse. MAAI-KO mice maintain high plasma and urine drug concentrations and do not biotransform DCA to monochloroacetate to a significant extent. Therefore, no alternative pathways for DCA clearance appear to exist in mice other than by MAAI-mediated biotransformation. DCA-nai;ve MAAI-KO mice accumulate very high levels of the tyrosine catabolites maleylacetone and succinylacetone, and DCA exposure did not significantly increase the levels of these compounds. MAAI-KO mice also have high levels of fumarylacetone and normal levels of fumarate. These results demonstrate that pharmacologic or genetic ablation of MAAI cause potentially toxic concentrations of tyrosine intermediates to accumulate in mice and perhaps in other species.
Ammini
Chandramohan V
CV
Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
Fernandez-Canon
Jose
J
Shroads
Albert L
AL
Cornett
Rachel
R
Cheung
Jang
J
James
Margaret O
MO
Henderson
George N
GN
Grompe
Markus
M
Stacpoole
Peter W
PW
D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000378:metabolism*; D019745:cis-trans-Isomerases / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D008298:Maleates; D012333:RNA, Messenger; C011905:maleoylacetic acid; D014443:Tyrosine; D003999:Dichloroacetic Acid; D019745:cis-trans-Isomerases; C021531:maleylacetoacetate isomerase