title: Sequestration of coenzyme A by the industrial surfactant, Toximul MP8. A possible role in the inhibition of fatty-acid beta-oxidation in a surfactant/influenza B virus mouse model for acute hepatic encephalopathy.
abstract: We have investigated the mechanistic basis of our recent observation that exposing young mice to an industrial surfactant potentiates the inhibition of fatty-acid beta-oxidation that occurs with subsequent virus infection (Murphy et al., Biochim. Biophys. Acta 1315, 208-216, 1996). In our mouse model for acute hepatic encephalopathy (AHE), neonatal mice were painted on their abdomens from birth to postnatal day 12 with nontoxic amounts of the industrial surfactant, Toximul MP8 (Tox), and then infected with a sublethal dose (LD30) of mouse-adapted human Influenza B (Lee) virus (FluB). Mortality in mice treated with Tox + FluB was significantly higher than that in mice treated with FluB alone. In vitro assays of hepatic beta-oxidation of [1-(14)C]palmitic and [1-(14)C]octanoic acids in the presence or absence of exogenous coenzyme A (CoA) indicated that Tox-mediated inhibition of oxidation was masked when CoA was added to the assays. FluB also inhibited beta-oxidation by 20-30%, however this effect was independent of exogenous CoA which suggested that it involved a different mechanism. Tox-mediated potentiation of the inhibitory effect was most obvious (> 80% inhibition) when assays were done without added CoA. Analysis of hepatic CoA and its esters indicated that levels of both free CoA and acetyl-CoA were significantly lower in mice that were painted with Tox for 12 days. Tox-dependent reductions of acetyl-CoA were transient and returned to normal values after cessation of painting, whereas those of CoA persisted. FluB infection alone significantly reduced hepatic acetyl-CoA and the magnitude of this reduction (> 30%) was not affected by pre-exposing the mice to Tox. Relative to control mice, levels of acid insoluble acyl-CoA esters were elevated significantly in FluB and Tox + FluB treated mice. Activation of both [1-(14)C]palmitic and [1-(14)C]octanoic acids was reduced in Tox-exposed mice at experimental day 12, but only when exogenous CoA was not included in the assay media; this effect appeared to persist after cessation of painting. Collectively, these data support the concept that Tox and FluB have independent effects on hepatic CoA metabolism that are associated with abnormalities in fatty-acid beta-oxidation. However, these do not fully explain the synergistic effect of the virus and chemical on beta-oxidation inhibition, which is a candidate co-mechanism for potentiation of mortality in this mouse model of AHE.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. mary.murphy@dal.ca
authors.forename: M G
authors.initials: MG
authors.lastname: Murphy
authors.forename: J F
authors.initials: JF
authors.lastname: Crocker
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Acott
authors.forename: H
authors.initials: H
authors.lastname: Her
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors*; D000105:Acetyl Coenzyme A / Q000032:analysis; D000102:Acetyl-CoA C-Acyltransferase / Q000037:antagonists & inhibitors*; D000214:Acyl Coenzyme A / Q000032:analysis; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases; D003065:Coenzyme A / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D003066:Coenzyme A Ligases / Q000032:analysis; D004195:Disease Models, Animal; D004655:Emulsions / Q000008:administration & dosage*; D004746:Enoyl-CoA Hydratase / Q000037:antagonists & inhibitors*; D006501:Hepatic Encephalopathy / Q000201:enzymology* / Q000401:mortality; D009981:Influenza B virus; D007535:Isomerases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D051379:Mice; D009930:Organic Chemicals; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors*; D013501:Surface-Active Agents / Q000008:administration & dosage*
chemical_list: D000214:Acyl Coenzyme A; D004655:Emulsions; D009930:Organic Chemicals; D013501:Surface-Active Agents; C038784:fatty acid oxidation complex; C019116:Toximul MP8; D000105:Acetyl Coenzyme A; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D007535:Isomerases; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases; D003066:Coenzyme A Ligases; D003065:Coenzyme A