SEQUESTRATION OF COENZYME-A BY THE INDUSTRIAL SURFACTANT, TOXIMUL MP8- A POSSIBLE ROLE IN THE INHIBITION OF FATTY-ACID BETA-OXIDATION IN ASURFACTANT INFLUENZA-B VIRUS MOUSE MODEL FOR ACUTE HEPATIC-ENCEPHALOPATHY

We have investigated the mechanistic basis of our recent observation t hat exposing young mice to an industrial surfactant potentiates the in hibition of fatty-acid beta-oxidation that occurs with subsequent viru s 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 wi th nontoxic amounts of the industrial surfactant, Toximul MP8 (Tox), a nd then infected with a sublethal dose (LD30) of mouse-adapted human I nfluenza B (Lee) virus (FluB). Mortality in mice treated with Tox + Fl uB was significantly higher than that in mice treated with FluB alone. In vitro assays of hepatic beta-oxidation of [1-C-14]palmitic and [1- C-14]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 b y 20-30%, however this effect was independent of exogenous CoA which s uggested that it involved a different mechanism. Tox-mediated potentia tion of the inhibitory effect was most obvious (> 80% inhibition) when assays were done without added CoA. Analysis of hepatic CoA and its e aters indicated that levels of both free CoA and acetyl-CoA were signi ficantly lower in mice that were painted with Tox for 12 days. Tox-dep endent reductions of acetyl-CoA were transient and returned to normal values after cessation of painting, whereas those of CoA persisted. Fl uB infection alone significantly reduced hepatic acetyl-CoA and the ma gnitude 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-C-14]palmitic and [1-C-14]octanoic acids w as reduced in Tox-exposed mice at experimental day 12, but only when e xogenous CoA was not included in the assay media; this effect appeared to persist after cessation of painting. Collectively, these data supp ort the concept that Tox and FluB have independent effects on hepatic CoA metabolism that are associated with abnormalities in fatty-acid be ta-oxidation. However, these do not fully explain the synergistic effe ct of the virus and chemical on beta-oxidation inhibition, which is a candidate co-mechanism for potentiation of mortality in this mouse mod el of AHE.