Title

Kupffer cell-mediated regulation of hepatobiliary transporters during drug-induced liver injury

Date of Completion

January 2008

Keywords

Health Sciences, Toxicology|Health Sciences, Pharmacology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Drug-induced liver injury results in altered mRNA and protein expression of hepatobiliary transporters in rodent models. Previous studies in our laboratory have focused on alterations in transporter expression as a potential adaptive response to acetaminophen-induced liver injury in mice. The work presented in this dissertation includes analysis of mRNA and protein expression of efflux transporters in human livers after toxic acetaminophen ingestion. Acetaminophen-damaged human livers exhibited increased expression of efflux transporter similar to previous findings in rodents. Both human and mouse liver exhibit increased P-glycoprotein (P-gp) and multidrug resistance protein 4 (MRP4/Mrp4) expression by acetaminophen. Since the signaling pathways responsible for these changes in transporter expression are unknown, the role of Kupffer cell-derived mediators in the regulation of transporter expression by hepatotoxicants was also investigated in this dissertation. Administration of liposome encapsulated clodronate to mice to eliminate Kupffer cells prior to acetaminophen treatment revealed that Kupffer cells protect from acetaminophen-induced hepatic necrosis. This study also showed that Kupffer cell function is required for Mrp4 induction. An in vitro approach utilizing co-cultures of primary mouse hepatocytes and Kupffer cells reproduced these in vivo findings. ^ Work in this dissertation also includes a comprehensive analysis of hepatobiliary transporter mRNA and protein expression following exposure to allyl alcohol. This periportal hepatotoxicant was selected for comparison to acetaminophen, since there are distinct populations of Kupffer cells in the different regions of the liver lobule with varied functions. Allyl alcohol treatment also resulted in up-regulation of efflux transport proteins with a concomitant down-regulation of uptake transport proteins. Interestingly, Mrp4 was selectively induced in centrilobular hepatocytes, and not in peripheral areas where necrosis occurs. These findings suggest a unique trait of centrilobular hepatocytes that enables them to up-regulate Mrp4 regardless of the zonal selectivity of the toxicant. Elimination of Kupffer cells prior to allyl alcohol exposure led to increased hepatotoxicity. However, Kupffer cell depletion did not alter the changes in transporters produced by allyl alcohol. In conclusion, this dissertation work serves to further characterize the expression and regulation of hepatobiliary transporters in response to toxicant exposure and it also describes the contribution of Kupffer cell function as a modulator of transporter expression during chemical-induced liver injury. ^

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