Rate and Route of Oxidation of Acrylic Acid to Carbon Dioxide in Rat Liver

Results of in vivo metabolism studies with acrylic acid (AA)have indicated that 60–80% of the administered dose isexcreted as CO₂ within 2–8 hr of oral dosing of rats;however, the pathway of AA metabolism to CO₂ in mammals hasnot been determined. To define this route, rat hepatocytes wereisolated and incubated with [1–¹⁴C]AA in a sealed vialmodified to trap evolved ¹⁴CO₂ Rapid oxidation of AA to CO₂was observed. Similar incubations conducted with rat liver homogenatesfortified with ATP, ADP, coenzyme A, carnitine, and malate alsoresulted in oxidation of AA. Mitochondria isolated from liverhomogenates were incubated with AA under the same conditionsand yielded higher rates of AA oxidation than homogenates. Additionof equimolar amounts of propionic acid, 3-hydroxypropionic acid,or 3-mer-captopropionic acid significantly inhibited the oxidationof AA by mitochondria. HPLC analysis of the mitochondrial incubationmixtures indicated that a single major metabolite, which coelutedwith 3-hydroxypropionate, accumulated in the solution. The resultsindicate that AA is rapidly incorporated into a mitochondrialpathway for propionic acid catabolism that results in the releaseof CO₂ and possible bioincorporation as acetate. This pathwayappears to be the principal route of detoxification of AA inmammals.     

Metabolism of Acrylic Acid to Carbon Dioxide in Mouse Tissues

Acrylic acid (AA) is acutely irritating at sites of initialcontact but causes little systemic toxicity probably due toits rapid metabolism to CO₂ and acetyl-CoA via a secondary pathwayof propionic acid catabolism. In this study, the rate of AAoxidation in 13 tissues of C3H mice was measured by incubatingtissue slices with [1-¹⁴C]AA and collecting ¹⁴CO₂. Oxidationof AA followed pseudo-Michaelis-Menten kinetics in the liver,kidney, and skin. Pseudo-K_m values were similar among thesetissues and averaged 0.67 mM. The maximal rate of AA oxidationin kidney, liver, and skin was 2890±436 (mean±SE,N=3), 616±62, and 47.9±5.8 nmol/hr/g, respectively.The remaining organs oxidized AA at rates less than 40% of therate in liver. Rates of metabolism in tissues from male andfemale mice were similar. 3-Hydroxypropionic acid was the onlymetabolite detected by high-performance liquid chromatographicanalysis following incubation of tissues with [1-¹⁴C]AA. Kidneyand liver also oxidized [2,3-¹⁴C]AA and [1-¹⁴C]acetate well,thus providing for the complete metabolism of AA carbons toCO₂. These results demonstrate that the rate of AA metabolismvaries significantly among mouse tissues and suggest that thekidneys and liver are major sites of detoxification of AA.