Date on Master's Thesis/Doctoral Dissertation

5-2013

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Barve, Shirish Shrikrishna

Committee Co-Chair (if applicable)

McClain, Craig

Committee Member

McClain, Craig

Committee Member

Joshi-Barve, Swati

Committee Member

Cave, Matthew C.

Committee Member

Kidd, LaCreis

Author's Keywords

HAART; Hepatic injury; Ethanol; Steatosis

Subject

Highly active antiretroviral therapy; Liver--Diseases; Drinking of alcoholic beverages--Health aspects; Drug-alcohol interactions

Abstract

Highly Active Antiretroviral Therapy (HAART) has led to a significant increase in the life expectancy of HIV patients; however, there are significant side effects including lipodystrophy and hepatotoxicity. Alcohol abuse is highly prevalent in HIV infected individuals and hence may be a significant negative cofactor in HAART induced hepatotoxicity. The present study examines the mechanisms underlying HAART and alcohol induced hepatotoxicity. The effects of HAART drugs (azidothymidine, and Indinavir sulphate) in combination with alcohol were examined in in vivo animal model. Alcohol and HAART drug interactions and hepatotoxicity were also assessed in-vivo using an animal model of chronic alcohol feeding. Mice were pair-fed liquid diets (Lieber DeCarli) containing 35% of calories as alcohol (alcohol-fed, AF) or as isocaloric maltose-dextrin (pair-fed, PF) for four weeks. In addition, HAART treatment groups received AZT (30mg/kg BW) and IDV (50mg/kg BW) by oral gavage for 2 weeks. Animals exposed to both alcohol and HAART developed increased visceral adiposity compared to pair-fed animal suggesting disturbances in lipid metabolism in these mice. Lipodystrophy was also evidenced by macro and microvesicular steatosis in the livers; elevated liver triglycerides and free fatty acids. Additionally, animals receiving combinations of alcohol and HAART exhibited increased inflammation and greater hepatic neutrophil infiltration. Overall, our data demonstrate that alcohol exacerbates HAART hepatotoxicity, and is a significant cofactor in the development of hepatic steatosis and liver injury.

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