Male Wistar rats were given ethanol chronically (20-30% of the energy as ethanol) in a nutritionally sufficient regimen. Controls received lipid as isoenergetic substitute for ethanol. Treatment lasted for 2 or 8 weeks. Hepatic protein synthesis was measured in fasted rats during a 32 min. continuous infusion of 'H-valine.After 2 weeks of treatment accumulation of hepatic protein was observed in the ethanol group, but there was no change in hepatic protein synthesis or morphology. After 8 weeks the rate of hepatic protein synthesis was decreased by 35% in the ethanol group, but there was no accumulation of protein and a slight accumulation of intracellular lipid droplets. Neither the subcellular distribution of incorporated 'H-valine, nor the activities and distributions of alcohol dehydrogenase and NADPH cytochrome c reductase were changed. Mitochrondrial cytochrome c oxidase activity was decreased in the ethanol group, and cytosolic and microsomal fractions showed higher cytochrome c oxidase activity in this group. Chronic ethanol treatment for 8 weeks had an adverse effect on general protein synthesis as well as on a specific enzyme in the liver in the absence of serious morphologic abnormalities.
Suspensions of liver cells isolated from perfused rat livers were incubated with antipyrine‐N‐methyl‐14C. Antipyrine was eliminated by first‐order kinetics during incubations for 3 hours with primary suspensions (parenchymal cells + non‐parenchymal cells) and suspensions of purified parenchymal cells. Antipyrine concentrations were unchanged when incubated with suspensions of non‐parenchymal cells, dead cells or medium only. At the end of incubation period, 4‐OH‐antipyrine and 3‐CH2OH‐antipyrine were detected mainly as the glucuronide or sulphate conjugates, and evidence for the N‐demethylation of antipyrine was also obtained. Half‐lives for elimination of antipyrine in primary cell suspensions were not significantly different from the half‐lives measured in parenchymal cell suspensions. This finding together with the lack of metabolism of antipyrine found in non‐parenchymal cell suspensions suggest that oxidation and conjugation of antipyrine is mainly confined to the parenchymal cells. There was significant inhibition of antipyrine metabolism in primary suspensions by phenylbutazone (1.6 × 10‐3 M), dexamethasone (2 × 10‐4 M) and ethanol (1.3 × 10‐2 M, 0.75 %0). We suggest that the use of primary suspensions of isolated rat liver cells provide a rapid and simple method for the study of factors influencing drug metabolism in the liver.
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