The relationship between mitochondrial activation and toxicity of some substituted carboxylic acids.
The activation of 4-bromocrotonic acid, 4-bromo-2-octenoic acid, valproic acid, and 3-methylglycidic acid by conversion to their CoA thioesters and the effects of these carboxylic acids on palmitoylcarnitine-supported respiration were studied with rat liver and rat heart mitochondria. 4-Bromocrotonic acid was activated by both liver and heart mitochondria, whereas 4-bromo-2-octenoic acid and valproic acid were only activated by liver mitochondria. 3-Methylglycidic acid was not a substrate of mitochondrial activation. All of the carboxylic acids that were activated also inhibited palmitoylcarnitine-supported respiration. 3-Methylglycidoyl-CoA was found to irreversibly inhibit 3-ketoacyl-CoA thiolase in a concentration-dependent and time-dependent manner. Together, these results lead to the conclusion that substituted medium-chain carboxylic acids, which enter mitochondria directly, may inhibit beta-oxidation as long as they are activated and perhaps further metabolized in the mitochondrial matrix to compounds that sequester CoA and/or inhibit beta-oxidation enzymes. Liver is more susceptible to inhibition by such xenobiotic carboxylic acids due to the broader substrate specificity of its mitochondrial medium-chain acyl-CoA synthetase (EC 6.2.1.2).
Yao
K W
KW
Department of Chemistry, City College of the City University of New York, NY 10031.
Mao
L F
LF
Luo
M J
MJ
Schulz
H
H
D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003065:Coenzyme A / Q000378:metabolism; D003437:Crotonates / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000633:toxicity; D008929:Mitochondria, Heart / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010172:Palmitoylcarnitine / Q000378:metabolism; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D014635:Valproic Acid / Q000378:metabolism / Q000633:toxicity; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity*
D002264:Carboxylic Acids; D003437:Crotonates; D004852:Epoxy Compounds; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D015262:Xenobiotics; C057780:4-bromo-2-octenoic acid; C034444:4-bromocrotonic acid; D010172:Palmitoylcarnitine; D014635:Valproic Acid; C087003:3-methylglycidic acid; D003065:Coenzyme A