Efficacy of urine bile acid as a non-invasive indicator of liver damage in rats

Abstract

-Estimation of liver damage is important in the pathophysiological and toxicological bile acids (UBA) in a rat model of liver disease. Thioacetamide (TAA)-treated rats were used in this study. Single intraperitoneal administration of high-dose TAA induces severe damage to the liver, and thus is used as a model of acute hepatitis. Continuous administration of low-dose TAA yields mild damand chronic administration of TAA was associated with a dose-dependent elevation of UBA. The elevation of UBA content correlated with the alteration of blood biochemical indicators, and UBA screening -with abnormal serum alkaline phosphatase (ALP) activity due to chronic liver damage, which was condemonstrated that measurement of UBA is a simple, non-invasive and effective method for the screening of cholestasis in TAA-treated rats. We suggest that UBA analysis may have potent applicability for monitoring the progress of liver damage in animal models of chronic liver disease, such as cirrhosis and hepatic encephalopathy.Bile acid, Urine, Liver, Cholestasis, Cirrhosis, ThioacetamideCorrespondence: Hiroshi Kawai (E-mail: hkawai@jiu.ac.jp) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.34, No.1, 27-38, 2009 Vol. 34 No. 1 27 the systemic circulation is small. The blood concentration -tions, but is increased in the case of a disorder in the liver or biliary tract (Dawson, 2002). Therefore, the serum bile acid level is a marker of liver disease, although it is not widely used as a routine screening test.Urine bile acids (UBA) have been detected in patients with hepatic disease since the 1950s (Rudman and Kendall, 1957; Makino et al et al., 1976;Almé et al., 1977;Simko et al., 1987;Batta et al., 1989; Shoda et al acids has been carried out mainly by gas or liquid chromatography -mass spectrometry (GC-MS, LC-MS) in recent studies. GC-MS and LC-MS can identify various structurally different bile acids precisely, and alteration of the composition of UBA can be analyzed. These methods, however, require complicated sample preparation, a long period of time, and a well-disciplined technician. A more simple and rapid method is needed for routine screening or analysis of a large number of samples. Recently, the direct enzymatic assay of urine sulfated bile acids (USBA) content was developed as a diagnostic tool (Matsui et al., 1996), and several reports revealed the clinical importance of USBA analysis (Obatake et al., 2002; Shinohara et al., 2005; Huang et al., 2007). Since a large portion of bile acids are sulfated in human urine (Palmer, 1967;Stiehl, 1974), USBA rather than non-sulfated UBA is useful in clinical application.UBA has also been analyzed in various animal species, such as hamsters (Galeazzi and Javitt, 1977), chimpanzees (Schweng et al., 1978), rabbits (Nakao et al., 1980), monkeys (Suzuki et al., 1985), and rats (Palmer, 1971; Takita et al., 1988;Lee et al., 2001). However, these studies focused on the alteration of metabolic ability of the liver and the pathogenic mechanisms of liver disease...

Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

“…This process may play a role in the pathogenesis of HE (Lozeva-Thomas, 2004). In a previous study, we observed decreased BTR in TAA-induced cirrhotic rats (Kawai et al, 2009; Table 1 in the current study). The decrease of BTR may be involved in the elevation of 5HT, NA, and their metabolites (Table 2); however, treatment with lactulose had no effect on BTR.…”

“…Compared with those of the control animals, the ALP activities and NH 3 levels were significantly increased in TAA0.5 rats, while the ALT activities, Alb contents and BTR were significantly reduced in TAA0.5 rats. These results indicate impairment of hepatic function with cholestasis (Kawai et al, 2009). In the group of lactulose-treated TAA rats, the activities of ALP and ALT, Alb contents, and BTR were significantly different from those of both the control and TAA0.5 groups, while the level of blood NH 3 tended to …”

“…2 and 3). Development of liver diseases such as cirrhosis (Kawai et al, 2009, and Table 1), and elevation of blood ammonia levels in TAA rats satisfy construct validity (Table 1). Amelioration of several symptoms by lactulose treatment satisfies predictive validity (Figs.…”

“…Acute administration of TAA at a high dose to rats induces HE, and this model meets the majority of criteria for type A HE (Zimmerman et al, 1989;Butterworth et al, 2009). On the other hand, chronic TAA treatment at a low dose to rats induces cirrhosis and hepatic tumors (Müller et al, 1988;Fontana et al, 1996;Kawai et al, 2009). The characteristic features of TAA-induced hepatotoxicity in rats resemble those of human cirrhosis (Müller et al, 1988;Dashti et al, 1989;Sato et al, 2000), and rats chronically treated with TAA exhibit memory impairment (Méndez et al, 2008a).…”

“…Induction of liver damage was performed by continuous administration of TAA in drinking water (0.3 or 0.5 g/l) for 20 weeks. The dose and the duration of TAA treatment was determined according to our previous study that rats developed cirrhosis by TAA treatment at 0.5 g/l for 16 weeks (Kawai et al, 2009). In the case of lactulose treatment, 2 g/kg of lactulose was orally administered once a day between 17:00 and 19:00 for 2 weeks.…”