Gerhard Hennighausen

The Course of Pancreatic Fibrosis Induced by Dibutyltin Dichloride (DBTC)

In summary, in addition to an acute interstitial pancreatitis the organotin compound DBTC induced a pancreatic fibrosis in rats. The course of the pancreatic fibrosis was studied 2-36 weeks after single i.v. treatment of rats with 6 or 8 mg/kg DBTC. The pancreatic fibrosis induced by DBTC differs from other experimental models of acute pancreatitis. Extensive infiltration by mononuclear cells is present in fibrotic areas without pancreatic atrophy or lipomatosis. The presence of chronic inflammatory lesions characterized by the destruction of exocrine parenchyma and fibrosis and in the later stages the endocrine parenchyma, indicate a chronic pancreatitis. In completion of the experimental model of the DBTC-induced acute interstitial pancreatitis in rats, the described late fibrotic effects on rat pancreas may be used as an experimental model of chronic pancreatitis.

The influence of ethanol on long-term effects of dibutyltin dichloride (DBTC) in pancreas and liver of rats

The present study was done to determine the additional influence of daily ethanol intake (15% in drinking water ad libitum) on long-term toxic effects of a single administration of dibutyltin dichloride (DBTC, 8 mg/kg b.w. i.v.) in pancreas and liver of rats. Pathohistological changes in pancreas, bile duct and liver as well as pathobiochemical parameters of pancreatitis (amylase and lipase activity), liver lesions (alkaline phosphatase activity and bilirubin) and fibrosis (hydroxyproline and hyaluronic acid) were measured 1 day and 1 to 24 weeks after DBTC- and DBTC/ethanol administration. DBTC alone induced in rats an acute interstitial pancreatitis as well as acute bile duct and liver lesions in the early experimental phase. Later on, the acute inflammatory processes in pancreas and liver took a chronic course resulting in pancreatic fibrosis and liver cirrhosis. Ethanol increased the toxic effects of DBTC on pancreas and liver during the acute and chronic course. In the acute phase lasting 1 day to 2 weeks, ethanol enhanced the DBTC toxicity on acinar cell and bilio-pancreatic duct epithelium as well as the formation of obstructive ductal plugs by necrotic cell debris. The obstruction and cholestasis in the DBTC/ethanol-group were significantly stronger as in the DBTC-group. The significant increase of hydroxyproline in urine and hyaluronic acid in serum of the DBTC/ethanol treated rats after 12 to 24 weeks was connected with a more severe chronic inflammatory fibrosis in pancreas and liver in comparison to the DBTC-treated group.

Repeated administration of a mild acute toxic dose of di-n-butyltin dichloride at intervals of 3 weeks induces severe lesions in pancreas and liver of rats

Di n-butyltin dichloride (DBTC) induced thymus atrophy, bile duct lesions, pancreatitis, and liver lesions in rats. Dependingondose [6and8mg/kgintravenous (i.v.) DBTC] andtime (1–24weeks),thelesionsinpancreasdevelopedto apancreaticfibrosisandthelesionsinlivertolivercirrhosis. A single i.v. administration of 4 mg/kg DBTC induces a mild interstitial pancreatitis after 2–4 days followed by a restitutio ad integrum after 21–28 days. In the present study,thelesionsofbiliopancreaticduct,pancreas,andliver of rats after repeated administration of 4 mg/kg DBTC i.v. at intervals of 3 weeks have been investigated. The histopathologicalchangesofpancreasandliverwereexaminedbylight microscopy1,4,and7daysand2,3,4,6,9,and12weeksafter administration of DBTC. Furthermore, pathobiochemical parameters of pancreatitis (amylase and lipase activity in serum), liver lesions (alkaline phosphatase activity and bilirubin in serum), and of fibrosis (hyaluronic acid in serum) were studied. Repeated administration of rats with DBTC (4mg/kgi.v.) atintervals of3weeks induced anacute interstitial pancreatitis and after 9–12 weeks, a pancreatic fibrosis and liver lesions (intrahepatic bile duct hyperplasia, inflammation in periportal tract, and necrosis). In serum, elevated levels of alkaline phosphatase, bilirubin, and hyaluronic acid were found. This study demonstrates that the organotin compound induces toxic effects on pancreas and liver of rats by repeated administration of lower doses at long intervals. The risk of exposure to organotin at long intervals should be considered.

Formation of Methanol and Formate in Wistar Rats after Oral Administration of Methylated Rapeseed Oil: A Fuel for Lamps

Low viscosity, low surface tension and low volatility are features of lamp oils contributing to chemical pneumonia that can occur after ingestion. Because lamp oils with such physico-chemical properties have been forbidden in the European Community from July 2000 onward, industry has developed different products, mostly based upon rapeseed oil. The fatty acids of these oils are methylated. The goal of this study is to demonstrate whether methanol is released in Wistar rats after oral administration of these new lamp oils. Applying a dose of 1 ml/kg body weight lamp oil, peak levels of methanol were reached at 1 h (54.6 ± 18.6 μg/ml), methanol was not detectable at 8 h. After the instillation of 4 ml/kg of lamp oil peak levels occurred at 2 h (189.2 ± 24.9 μg/ml). The metabolite formate increased with time, and was highest at 8 h after the administration of 1 ml/kg body weight lamp oil (32.9 ± 2.9 μg/ml). Starvation before the administration of 1 ml/kg body weight lamp oil decreased the methanol serum concentrations, but the differences were not significant. Based upon these experimental data in rats, it can be concluded that in humans small amounts of methanol will be released after ingestion of these lamp oils. As these products are mainly ingested accidentally by toddlers in low quantities, the risk of a methanol intoxication seems to be very low.

Meso-2,3-dimercaptosuccinic acid increases the inhibition of glutathione S-transferase activity from rat liver cytosol supernatants by di-n-butyltin dichloride.

Di-n-butyltin dichloride (DBTC) and tricyclohexyltin chloride (TCHTC) inhibited the glutatione S-transferase activity of rat liver cytosolic supernatants to-wards 1-chloro-2,4-dinitrobenzene. Meso-2,3-dimercaptosuccinic acid increased inhibition of glutathione S-transferase by DBTC but lowered inhibition of the enzyme by TCHTC.

Selectivity of Antiproliferative Effects of Dialkyltin Compounds in Vitro and in Vivo

The inhibition of proliferation of thymocytes in vivo and in vitro is one of the earliest and most prominent biological effects caused by dialkyltin compounds. A single dose of dibutyltin dichloride (DBTC) or dioctyltin dichloride (DOTC) decreased the mitotic activity of thymocytes in mice and rats 1 to 7 days after administration. The inhibition of the mitotic rate of thymocytes was followed by a decrease of the thymus weight and thymocyte count. There was a difference in the time course of thymus atrophy induced by DOTC or glucocorticoids (Fig. 1). This difference could be explained by the additional cytolytic activity of glucocorticoids whereas the dialkyltin compounds induce the thymus atrophy solely by antiproliferative activity.