J. Werner et al., Linkage of oxidative and nonoxidative ethanol metabolism in the pancreas and toxicity of nonoxidative ethanol metabolites for pancreatic acinar cells, SURGERY, 129(6), 2001, pp. 736-744
Background. Alcohol abuse is a major cause of pancreatic damage. Recent exp
erimental evidence suggests that fatty acid ethyl esters (FAEE), nonoxidati
ve ethanol metabolites, injure pancreatic acinar cells. Linkage between oxi
dative and nonoxidative metabolism of ethanol in the pancreas may contribut
e to increased FAEE levels.
Methods. To study the association between oxidative and nonoxidative ethano
l metabolism, FAEE concentration and FAEE synthase activity in rat pancreat
ic and liver homogenates incubated with ethanol were evaluated with and wit
hout inhibitors of oxidative ethanol metabolism. For toxicity studies, tryp
sinogen activation peptide synthesis as a measure of pancreatic cell injury
was quantitated in unstimulated and cerulein-stimulated isolated pancreati
c acinar cells incubated with ethanol or FAEE.
Results. Inhibition of oxidative ethanol metabolism results in a 2- to 3-fo
ld increase in nonoxidative ethanol metabolism to FAEE in pancreas and in l
iver. Both ethanol and FAEE induce increased intracellular trypsinogen acti
vation by more than 50% in the presence of physiologic concentrations of ce
rulein in vitro.
Conclusions. These findings demonstrate that the inhibition of oxidative et
hanol metabolism results in an increase in flux through the nonoxidative pa
thway and support the proposition that alcohol-induced pancreatic injury is
mediated at least in part by FAEE, which are important products of pancrea
tic ethanol metabolism.