CHANGES IN THE LIVER PROTEIN PATTERN OF FEMALE WISTAR RATS TREATED WITH THE HYPOGLYCEMIC AGENT SDZ PGU 693

SDZ PGU 693 acts as a hypoglycemic agent by stimulating glucose utilis ation in insulin-sensitive peripheral tissues, such as skeletal muscle and fat. In a 28 day toxicity study the compound was found to induce hepatocellular hypertrophy in Wistar rats treated with 300 mg/kg/day. To gain insights into the pathomechanism of these alterations, aliquot s of liver samples from control and treated female Wistar rats were se parated by two-dimensional protein gel electrophoresis and the digitiz ed images of the protein patterns were searched for protein abundance changes. Significant treatment-related quantitative changes (P < 0.001 ) were found in 29 liver proteins. Major increases were observed in se veral microsomal proteins, including NADPH cytochrome P-450 reductase, cytochrome b5 and serine protease inhibitor. The changes in the cytoc hrome related enzymes, both known co-factors of the P-450 enzyme syste m, strongly suggest that SDZ PGU 693 induces microsomal proliferation and induction of the P-450 enzyme system. Decreases were observed in a series of mitochondrial proteins, such as F(1)ATPase-delta subunit an d ornithine aminotransferase precursor as well as in several cytosolic proteins such as the liver fatty acid binding protein, arylsulfotrans ferase and the senescence marker protein-30. The changes in F(1)ATPase -delta subunit and liver fatty acid binding protein together suggest a down-regulation of the mitochondrial liver fatty acid metabolism, lik ely reflecting the pharmacological action of the compound. These resul ts show that SDZ PGU 693 produces a complex pattern of gene expression changes which give insights into the molecular mechanisms of both its pharmacological action and a toxic response.