Cholestasis in rats

Huang, L., Smit, J. W., Meijer, D. K., Vore, M., Mrp2 is essential for estradiol-17beta( beta-D-glucuronide)-induced cholestasis in rats, Hepatology 2000, 32, 66-72. 

Soroka CJ, Lee JM, Azzaroli F, Boyer JL. Cellular localization and up-regula-tion of multidrug resistance-associated protein 3 in hepatocytes and cholangio-cytes during obstructive cholestasis in rat liver. Hepatology 2001 33(4) 783 791. 

Bouchard et al. (1993) induced cholestasis in rats by treatment with 17-a-ethinyl estradiol and studied the influence of oral treatment with ursodeoxycholic and tau-roursodeoxycholic acids. 

Bouchard G, Yousef IM, Tuchweber B (1993) Influence of oral treatment with ursodeoxycholic and tauroursodeoxy-cholic acids on estrogen induced cholestasis in rats Effects on bile formation and liver plasma membranes. Liver 13 193-202... 

Jl. Javitt, N. B., Cholestasis in rats ittduced by taurolithocholate. Nature (London) 210, 1262-1263 (1966). 

Kaksis, C., and Yousef, I. M., Mechanism of cholic acid protection in lithocholate-induced intrahepatic cholestasis in rats. Gastroenterology 78, 1402-1411 (1980). Kallberg, M., and Tobiasson, P., Determination of cholic and chenodeoxycholic acid in serum. Evaluation of two commercial radioimmunoassay methods. J. Clin. Chem. Clin. Biochem. 18, 491-495 (1980). 

De Lamirande E, Plaa GL. 1978. Role of manganese, bilirubin and sulfobromophthalein in manganese-bilirubin cholestasis in rats (40189). Proc Soc Exp Biol Med 158 283-287. 

Although the highest concentrations of this membrane-localized enzyme are in the kidney and pancreas, increases of plasma GGT have been reported following cholestasis in rats, where GGT changes are more specific than those observed for ALP, even though the basal plasma GGT levels are very low (Huseby and Torstein 1978 Leonard, Neptun, and Popp 1984 Evans 1986 also see Chapter 2). Plasma GGT activity is rarely altered by primary hepatocellular toxicity in laboratory animals. 

C. C. Roy, Lithocholate cholestasis- sulfated glycolitho-cholate induced intrahepatic cholestasis in rats, Gastroenterol., 80 233 (1981). 

Moslen. M.T.. Poisson. L.R. Reynolds, E.S. (1985) Cholestasis and increased biliary excretion of inulin in rats given 1,1-dichloroethylene. Toxicology, 34, 201-209... 

Denk GU, Soroka CJ, Takeyama Y, Chen WS, Schuetz JD, Boyer JL. Multidrug resistance-associated protein 4 is up-regulated in liver but down-rregulated in kidney in obstructive cholestasis in the rat. J Hepatol 2004 40 585-591. 

Bohme M, Muller M, Leier I et al. (1994) Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology 107 255-265 Boyer JL, Meier PJ (1990) Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Methods Enzymol 192 517-533... 

Crocenci, F.A., Sanchez-Pozzi, E.J., Pellegrino, JJM., Rodrignez-Garay, E.A., Mottino, A.D., Roma, M.G. Preventive effect of silymarin against taurolithocholate-induced cholestasis in the rat. Biochem. Pharmacol. 2003 66 355-364... 

The already mentioned proteins OCTI and OCT3 transport small cationic substances, such as tetraalkyl ammonium compounds, polyamines such as spermine, monoamino-neurotransmitters, or N-methyl-nicotinamide across the basolateral plasma membrane [56]. OCTs play a key role in the distribution of cationic drugs and, therefore, drug interactions at the transporter level may become clinically relevant, as compounds with high affinity, such as prazosin or phenox-ybenzamine, may affect the excretion of other substrates. Certain liver diseases or obstructive cholestasis may result in alterations of hepatic clearance via these transporters. In rats, a 7-day bile duct ligation resulted in a marked downregulation of Octi and an increased hepatic accumulation of the Octi substrate tetraethylammonium [57]. 

TNAP is expressed in human hepatocytes, and bile acids increase its activity [93] and secretion in the bile [94]. TNAP in rat hepatocytes is predominantly localized in the bile canalicular domain of the plasma membrane [95, 96], but can be addressed to the baso-lateral membrane in the presence of high levels of bile acid [97]. In contrast, mouse hepatocytes do not express TNAP [98]. In humans, liver TNAP may be expressed both at the sinusoidal and biliary pole of the hepatocyte. This explains why a significant proportion of TNAP activity in the circulation of healthy individuals originates from the liver. TNAP serum levels are of major clinical relevance as a marker of cholestasis. AP levels increase due to retrograde reflux of biliary alkaline phosphatase, enhanced hepatic synthesis and enzyme release into the serum, and induction of the intestinal alkaline phosphatase form [94, 99, 100]. 

Increased serum bile acids, suggesting cholestasis, were observed in rats treated with 1.57 mg selenium/kg/day as sodium selenate in drinking water for 13 weeks, but no effects were noted at 0.92 mg/kg/day (NTP 1994). In a 13-week drinking water study, hepatic effects were not observed in mice treated with sodium selenate at 7.17 mg selenium/kg/day, in mice treated with sodium selenite at doses up to 3.83 mg selenium/kg/day, or in rats treated with sodium selenite at doses up to 1.67 mg selenium/kg/day (NTP 1994). Increased serum aspartate aminotransferase and alanine aminotransferase activities were observed in mice treated by gavage with selenocystine at doses of 9.4 mg selenium/kg/day for 30 days (Sayato et al. 1993) or 4.7 mg selenium/kg/day for 90 days (Hasegawa et al. 1994). No effects on liver enzymes were observed in mice treated with selenocystine at 4.7 mg selenium/kg/day for 30 days (Sayato et al. 1993) or at 2.5 mg selenium/kg/day for 90 days (Hasegawa et al. 1994). Chronic dietary administration of selenium as seleniferous com or wheat at doses ranging from 0.25 to 0.50 mg/kg/day for 24 months produced cirrhosis of the liver in rats (Nelson et al. 1943). 

Chlorpromazine decreases BSP excretion in rats (C22) and in man (D8). However, in mice, the biliary excretion of BSP is not reduced by this drug (El). Chlorpromazine does not inhibit the clearance of either bilirubin or indocyanine green (H5), but its action and that of other phenothiazines (e.g., promazine, trifluoroperazine, prochlorperazine, and pecazine) is complex. These drugs, cause a cholestatic reaction with a transient cholestatic hepatitis (PIO, W4, Zl), with an incidence of approximately 1%. Thus, the effect on BSP retention may be a reflection of the cholestasis induced by these drugs. Their action may also be due to increased membrane permeability (H5). 

In hepatic studies, plasma GGT can be used as an indicator of cholestasis, even in rats where plasma GGT levels are normally very low (often less than 2 lU/L). The use of GGT as a marker of enzyme induction and in the presence of hepatic tumors is less predictive in laboratory animals compared with data from human studies (Braun et al. 1987 Batt et al. 1992). GGT synthesis is induced in the liver by some xenobi-otics (e.g., barbiturate) and by compounds that act via the thyroid on the liver (e.g., propylthiouracil and some glucocorticoids) (Sulakhe, Tran, and Pulga 1990). 

Yabe, T., and A. Kast. 1988. The optimum pH of serum alkaline phosphatase after induced cholestasis in the male rat, mouse and rabbit. Journal of Toxicological Sciences 13 179-191. 

Ishihara K et al (2009) Identification of urinary biomarkers useful for distinguishing a difference in mechanism of toxicity in rat model of cholestasis. Basic Clin Pharmacol Toxicol 105(3) 156-166... 

Surgical models also exit for evaluation of hepatic fibrosis. The most common method employed is ligation of the common bile duct in rats or mice. The subsequent response involves not only fibrosis but also proliferation of biliary epithelial cells, oval cells, portal inflammation, and, of course, cholestasis. With time, there is progression to biliary cirrhosis and hepatic failure. Relatively high mortality... 

Bohme, M., Muller, M., Leier, L, Jedhtschky, G., Keppler, D. 1994. Cholestasis caused hy inhihition of the adenosine triphosphate-dependent hUe salt transport in rat liver. Gastroenterology, 107, 255—65. 

Belknap. W.M. Balistreri, W.F., Suchy, F.J. and Miller, P. Physiologic cholestasis. II Serum bile acids reflect the development of the enterohepatic circulation in rats. Hepatology J. 613 (1981). 

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