technetium-tc-99m-mebrofenin and Chemical-and-Drug-Induced-Liver-Injury

Many diseases are associated with cytokine release after inflammatory infiltration, which perturbs organ function. Radioligands capable of noninvasive tracking to assess the integrity of specific biochemical pathways offer potent ways to establish such perturbing mechanisms.. To demonstrate regulation of hepatobiliary transport in disease, we used (99m)Tc-mebrofenin in a carbon tetrachloride-induced liver injury model in Fischer 344 rats. Healthy rats served as control animals. Image analysis was used to determine (99m)Tc-mebrofenin handling. Liver tests and histologic analysis were used for grading liver injury and hepatic fibrosis. To address the role of inflammatory cytokines, we used in vitro assays with (99m)Tc-mebrofenin-loaded primary rat hepatocytes.. In healthy rats, (99m)Tc-mebrofenin was promptly excreted, and after 1 h only 20% +/- 5% (mean +/- SD) of peak (99m)Tc-mebrofenin activity remained in the liver. In contrast, rats treated with carbon tetrachloride for 1 or 3 mo showed 84% +/- 5% and 80% +/- 7% (mean +/- SD), respectively, of peak (99m)Tc-mebrofenin activity in the liver after 1 h (P < 0.001). Abnormal (99m)Tc-mebrofenin transport was associated with necroinflammatory activity and not hepatic fibrosis. This was examined directly in animals, where withdrawal of carbon tetrachloride for 2 wk after significant liver injury produced loss of inflammatory activity without affecting hepatic fibrosis. In this situation, (99m)Tc-mebrofenin transport returned to normal, indicating a central role of inflammatory activity in this process. In vitro assays showed impairment in (99m)Tc-mebrofenin excretion after incubation of cultured hepatocytes with interleukin-6 and further impairment with interleukin-6 plus tumor necrosis factor-alpha.. The findings indicate that inflammatory cytokines regulate (99m)Tc-mebrofenin transport. This cytokine-mediated process establishes a paradigm for identifying and monitoring organ inflammation, including in viral or alcoholic hepatitis, fatty liver disease, allograft rejection, and responses to gene therapy vectors.

Topics: Aniline Compounds; Animals; Bile Ducts; Biological Transport, Active; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytokines; Glycine; Imino Acids; Liver; Metabolic Clearance Rate; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Inbred F344; Tissue Distribution

This study was carried out to see the hepatobiliary clearance of 99m Tc-Mebrofenin radiopharmaceutical in D-galactosamine induced hepatic rats. Furthermore, protective effect of turmeric extract has been studied in these hepatitis rats. Hepatitis was induced with intraperitoneal injection of D-galactosamine (400 mg/kg b. wt) in these rats. 1% turmeric extract was given along with their normal diet for 15 days. Turmeric extract treatment significantly increased the hepatic uptake of radioactivity and accelerated the excretion of 99m Tc-Mebrofenin as compared to control rats. (P < 0.001). In D-galactosamine administered rats, a significant delay was observed in 99m Tc-Mebrofenin excretion as compared to controls. However, D-galactosamine administered rats, pretreated with turmeric extract or concurrently treated with turmeric extract showed a near normal pattern of 99m Tc-Mebrofenin excretion. Hence, it can be suggested that turmeric extract may improve the liver function by detoxification.

Topics: Alanine Transaminase; Alkaline Phosphatase; Aniline Compounds; Animals; Aspartate Aminotransferases; Bile; Chemical and Drug Induced Liver Injury; Curcuma; Galactosamine; Glycine; Imino Acids; Injections, Intravenous; Liver; Liver Function Tests; Male; Organotechnetium Compounds; Phytotherapy; Plant Roots; Radiopharmaceuticals; Rats; Rats, Wistar; Tissue Distribution

Extraction of the hepatobiliary radiopharmaceutical 99mTc-N-(3-bromo-2,4,6-trimethyacetanilide) iminodiacetic acid (mebrofenin; Choletec, Squibb Diagnostic, Princeton, NJ) by the liver may be used as an index of hepatocellular function. The hepatic parenchymal cells extract mebrofenin from the blood using the same active transport mechanism as bilirubin.. In this study, we induced hepatocellular disease by administering a hepatotoxic drug and compared the hepatic extraction efficiency (HEE), measured directly from an afferent injection of 99mTc-mebrofenin, to quantitative histopathology and to serum biochemistry analysis.. The baseline HEE was 95.9% +/- 2.71% (mean +/- s.d.). Dogs that were affected by the hepatotoxic drug had reduced HEE. HEE correlated well to the severity of histologic lesions (r = -0.83, p = 0.003). HEE also correlated well to the increases in the activities of alanine aminotransferase (ALT; r = -0.85, p = 0.002) and aspartate aminotransferase (AST; r = -0.89, p = <0.001), the concentration of fasting bile acid (r = -0.97, p = <0.001), bilirubin (r = -0.92, p = <0.001) and, to a lesser degree, to the activities of alkaline phosphatase (Alk Phos; r = -0.73, p = 0.016). HEE had higher correlation coefficients to the serum biochemistry analysis than did the quantitative liver histopathology.. Hepatic extraction of 99mTc-mebrofenin is a good predictor of the severity of hepatocellular damage in toxic-induced liver disease.

Topics: Aniline Compounds; Animals; Arsenamide; Chemical and Drug Induced Liver Injury; Dogs; Female; Glycine; Imino Acids; Liver; Liver Function Tests; Male; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals