ABSTRACT
Accumulating evidence pointing to mitochondria as critical participants in the control
of apoptotic and necrotic cell death and in the development of specific disease states
has led to a renaissance on the study of these or-ganelles. Because mitochondria are
the major consumers of molecular oxygen within cells, they stand as one of the most
important generators of reactive oxygen species and therefore constitute potential
targets of therapeutic intervention in pathologic states in which oxidative stress
originates from these organelles. In this regard, mitochondria are specific targets
of ethanol intoxication, thereby leading to reported morphologic and functional alterations
of mitochondria. Because mitochondria are also indispensable for the maintenance of
cell functions, their dysfunction induced by ethanol may be a key event in the development
of alcoholic liver disease. Indeed, chronic ethanol feeding in experimental animals
has been reported to cause a selective deficiency in the availability of reduced glutathione
(GSH) in mitochondria due to the impaired functioning of the specific mitochondrial
carrier that translocates GSH from cy-tosol into the mitochondrial matrix. Such a
selective depletion sensitizes hepatocytes from chronic ethanol-fed animals to the
oxidative effects of cytokines, e.g., tumor necrosis factor (TNF). Restoration of
mitochondrial GSH by the in vivo administration of S-adenosyl-L-methionine or the
in vitro use of GSH ethyl ester, prevents the susceptibility of hepatocytes to TNF.
Although the nature of this specific carrier has not yet been uncovered, the elucidation
of the mechanisms whereby ethanol leads to its impaired activity may provide important
clues as to its function and mechanism of action, which in turn may be useful toward
the definitive characterization and identification of this important carrier.
KEY WORDS
cytokines - oxidative stress - ethanol metabolism - signal transduction
