Elevated levels of plasma homocysteine (Hcy) are believed to be involved in several health problems, including liver fibrosis. However, the mechanism of Hcy induced liver injury remains to be further investigated. Although all hepatic cell types are involved in fibrogenesis, the activation and proliferation of hepatic stellate cells (HSCs) are considered to be central events. Moreover, it is reported that bone morphogenetic proteins (BMPs) play an important role in cell proliferation, differentiation and apoptosis. In this experiment, we examined the expression of BMPs in rat liver with hyperhomocysteinemia (HHcy) and in HSC cell lines at both mRNA and protein levels. The principal findings suggest that the expression of BMP-13 was significantly reduced in the liver of rats after 4 and 12 weeks of HHcy compared with that in control. Furthermore, there were significant increase in cell proliferation and modification of HSCs after Hcy treatment. In conclusion, a long term high methionine diet can cause a reduction of BMP-13 in the liver. The reduction of BMP-13 in the liver may contribute to liver injury induced by a high methionine diet.

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Elevated levels of plasma homocysteine (Hcy) are believed to be involved in several health problems, including liver fibrosis. However, the mechanism of Hcy induced liver injury remains to be further investigated. Although all hepatic cell types are involved in fibrogenesis, the activation and proliferation of hepatic stellate cells (HSCs) are considered to be central events. Moreover, it is reported that bone morphogenetic proteins (BMPs) play an important role in cell proliferation, differentiation and apoptosis. In this experiment, we examined the expression of BMPs in rat liver with hyperhomocysteinemia (HHcy) and in HSC cell lines at both mRNA and protein levels. The principal findings suggest that the expression of BMP-13 was significantly reduced in the liver of rats after 4 and 12 weeks of HHcy compared with that in control. Furthermore, there were significant increase in cell proliferation and modification of HSCs after Hcy treatment. In conclusion, a long term high methionine diet can cause a reduction of BMP-13 in the liver. The reduction of BMP-13 in the liver may contribute to liver injury induced by a high methionine diet.

Clofibric acid (CA), an anti-hyperlipidaemic agent, possesses a carboxylic acid functional group and is metabolised to an acyl glucuronide conjugate (CAG). Acyl glucuronides are intrinsically reactive metabolites of carboxylate drugs, and are capable of undergoing hydrolysis, intramolecular rearrangement, and covalent binding to macromolecules. / The purpose of this study was to determine the hepatic disposition of CA and CAG using the isolated perfused rat liver (IPRL). A pharmacokinetic model was devised to interpret the results. / Livers of male Sprague-Dawley rats were perfused under single-pass conditions with protein- and erythrocyte- free perfusate, containing CA, at a constant flow rate of 30mL/min. Outflow samples were collected into tubes containing ortho-phosphoric acid solution, which stabilised the samples, and analysed using HPLC method. / A study of the effect of CA concentration in perfusate medium on the hepatic disposition of the compound suggested that the pharmacokinetics of CA are linear from 0.2 to 1.0mg/L. Above this inflow concentration (at CA 5mg/L), the hepatic extraction ratio (E) and hepatic clearance (CL) decreased significantly (P < 0.05). Results of a drug interaction study indicated that probenecid (0.02mM) co administration significantly reduced (P < 0.05) the E and CL of CA, while paracetamol (0.02mM) did not change the pharmacokinetic parameters of CA. / The study improved our understanding of CA disposition in the liver and the potential impact of CA and probenecid coadministration. / Thesis (MApSc(Pharmacy))--University of South Australia, 2006.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available in print.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (M. Med. Sc.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 54-60)

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 97-108) Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 97-108) Also available online.