Drug-Induced Models of Cholestasis and Lysosomes

Abstract

Cholestasis, caused by the interrupted excretion of bile, resulting in an accumulation of bile products in the body fluids is characteristic of many human liver diseases (Sherlock & Dooley, 1997). Experimental animal models of cholestasis allow the understanding of pathophysiological mechanisms involved and their clinical correlates (Chang et al., 2005; Chandra & Brower, 2004). The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis (Rodriguez-Garay, 2003). Drug-induced cholestasis was described during treatment by different drugs in medical clinic and in experimental research. In experimental medicine, αnaphthylisothiocyanate (ANIT) treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. The animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms which operate on liver cells. Continuous bile formation is an important function of the liver, and bile is used as a vehicle for the secretion of bile acids and the excretion of lipophilic endoand xenobiotics (Meier and Stieger, 2000; Hsien et al., 2006). Molecular and cellular mechanisms of intrahepatic cholestasis development are important for understanding of role of different factors in this process and effective therapy. Lysosomes are connected with bile secretion, however their role in cholestasis development is still not clear. Human bile revealed high activity of lysosomal enzymes (β-galactosidase, β-N-acetylglucosaminidase, acid phosphatase) which are suggested to be secreted from lysosomes localized in peribiliar zone of hepatocytes (Korolenko et al., 2007). We tested the hypothesis that impaired lysosomal secretion is related to cholestasis development. Earlier in some works it was shown that in mice and rats increased activity of lysosomal enzymes in bile was connected with their increased secretion.