Livers from Charles River rats during and after treatment with phenobarbital were studied in order to investigate possible mechanisms involved in the elimination of excess smooth endoplasmic reticulum. The most pronounced structural change during compound administration was proliferation of smooth endoplasmic reticulum; depletion of glycogen and an increase in lipid deposits were also observed. After termination of treatment, these changes were reversed. The appearance of an increased number of autophage vacuoles and lysosomes plus the localization of acid phosphatase reaction product in these bodies suggests The administration of phenobarbital is known to increase the activity of drug-metabolizing enzymes in the liver accompanied by hepatic ultrastructural changes (5-7, 1 1, 18, 23, 25, 31, 32, 36, 37, 39), the most prominent ofwhich is the proliferation of smooth endoplasmic reticulum. Following the cessation of compound administration, the smooth endoplasmic recticulum eventually returns to normal amounts. Regarding the mechanism of membrane removal, one report proposed that the excess smooth endoplasmic reticulum was sequestered within autophage vacuoles and then degraded by the action of lysosomal enzymes (5). According to another report (3 1), an association between the removal of smooth endoplasmic reticulum and increased autophage activity was not observed. The purpose of this study is to investigate mechanisms involved in the elimination of smooth endoplasmic reticulum, including the role ofacid phosphatase enzyme. ?5l)' , OF EXCESS SMOOTH ENDOPLASMIC RETICULUM 1005

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Lipid amphiphile toxicity may be an important contributor to myocardial injury, especially during ischemia/reperfusion. In order to investigate directly the potential biochemical and metabolic effects of amphiphile overload on the functioning heart muscle cell (myocyte), a novel model of nonesterified fatty acid (NEFA)-induced myocyte damage has been defined. The model uses intact, beating neonatal rat myocytes in primary monolayer culture as a study object and 5-(tetradecyloxy)-2-furoic acid (TOFA) as a nonmetabolizable fatty acid. Myocytes incubated with TOFA accumulated it as NEFA, and the consequent NEFA amphiphile overload elicited a variety of cellular defects (including decreased beating rate, depletion of high-energy stores and glycogen pools, and breakdown of myocyte membrane phospholipid) and culminated in cell death. The amphiphile-induced cellular pathology could be reversed by removing TOFA from the culture medium, which resulted in intracellular TOFA "wash-out." Although the development and severity of amphiphile-induced myocyte injury could be correlated with both the intracellular TOFA/NEFA content (i.e., the level of TOFA to which the cells were exposed) and the duration of this exposure, removal of amphiphile overload did not inevitably lead to myocyte recovery. TOFA had adverse effects on myocyte mitochondrial function in situ (decoupling of oxidative phosphorylation, impairing respiratory control) and on myocyte oxidative catabolism (transiently increasing fatty acid beta oxidation, citric acid cycle flux, and glucose oxidation). The amphiphile-induced bioenergetic abnormalities appeared to constitute a state of "metabolic anoxia" underlying the progression of myocyte injury to cell death. This anoxic state could be ameliorated to some extent, but not prevented, by carbohydrate catabolism.

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