Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes.

Tetracycline is known to cause hepatic dysfunction in humans by inducing steatosis. Accumulation of fat in the liver could result from biochemical effects at various levels in the sequence from protein and triglyceride synthesis to lipoprotein secretion. The effects of tetracycline on the synthesis and secretion of triglycerides and proteins were studied in isolated rat hepatocytes surviving in suspension for up to 2.5 hr. Interpretation of the results obtained for tetracycline was made by comparison with results obtained, under the same experimental conditions, for the well-known steatogenic compounds, cycloheximide and colchicine. The data indicate that tetracycline produces a concentration-dependent inhibition of 14C-triglyceride secretion without affecting triglyceride synthesis. This inhibition explains the intracellular triglyceride accumulation. However, tetracycline does not affect protein secretion. Furthermore, it was demonstrated that the effect of tetracycline on protein synthesis was not related to inhibition of triglyceride release. In conclusion, it is proposed that the effect of tetracycline could be at the level of the association between triglycerides and apoproteins to form lipoproteins.