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.