Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Medium-chain acyl-CoA dehydrogenase- and enoyl-CoA hydratase-dependent bioactivation of 5,6-dichloro-4-thia-5-hexenoyl-CoA.

Authors: Fitzsimmons, M E; Thorpe, C; Anders, M W

Published In Biochemistry, (1995 Apr 04)

Abstract: 5,6-Dichloro-4-thia-5-hexenoic acid (DCTH) is a potent hepato- and nephrotoxin that induces mitochondrial dysfunction in rat liver and kidney. Previous studies indicate that DCTH undergoes fatty acid beta-oxidation-dependent bioactivation. The objectives of the present experiments were to elaborate the bioactivation mechanism of DCTH and to examine the interaction of the coenzyme A thioester of DCTH (DCTH-CoA) with the medium-chain acyl-CoA dehydrogenase. In the presence of the terminal electron acceptor ferricenium hexafluorophosphate (FcPF6), DCTH-CoA was oxidized by the medium-chain actyl-CoA dehydrogenase to give 5,6-dichloro-4-thia-trans-2,5-hexadienoyl-CoA. Enoyl-CoA hydratase catalyzed the conversion of 5,6-dichloro-4-thia-trans-2,5-hexadienoyl-CoA to 5,6-dichloro-4-thia-3-hydroxy-5-hexenoyl-CoA, which eliminated 1,2-dichloroethenethiol and gave malonyl-CoA semialdehyde as a product. Chloroacetic acid was detected as a terminal product derived from 1,2-dichloroethenethiol. Incubation of DCTH-CoA with the medium-chain acyl-CoA dehydrogenase in the absence of FcPF6 gave 3-hydroxypropionyl-CoA as the major product and resulted in the irreversible inactivation of the enzyme. Under these conditions, DCTH-CoA apparently undergoes a beta-elimination reaction to give 1,2-dichloroethenethiol and acryloyl-CoA, which is hydrated to give 3-hydroxypropionyl-CoA as the terminal product. The beta-elimination product 1,2-dichloroethenethiol may yield reactive intermediates that inactivate the dehydrogenase. Enzyme inactivation was rapid, DCTH-CoA concentration-dependent, and blocked by octanoyl-CoA, but not by glutathione. The medium-chain acyl-CoA dehydrogenase was not inactivated by acryloyl-CoA, and little inactivation was observed in the presence of FcPF6. These results show that DCTH-CoA is bioactivated by the mitochondrial fatty acid beta-oxidation system to reactive intermediates. This bioactivation mechanism may account for the observed toxicity of DCTH in vivo and in vitro.

PubMed ID: 7703241 Exiting the NIEHS site

MeSH Terms: Acetates/metabolism; Acyl Coenzyme A/metabolism; Acyl Coenzyme A/pharmacokinetics*; Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenases/antagonists & inhibitors; Acyl-CoA Dehydrogenases/metabolism*; Animals; Biotransformation; Chromatography, High Pressure Liquid; Enoyl-CoA Hydratase/metabolism*; Flavin-Adenine Dinucleotide/analogs & derivatives; Flavin-Adenine Dinucleotide/metabolism; Hydrogen-Ion Concentration; Hydrolysis; Kidney/enzymology; Magnetic Resonance Spectroscopy; Malonyl Coenzyme A/metabolism; Mitochondria/enzymology; Oxidation-Reduction; Spectrophotometry; Swine

Back
to Top