Graduation Year

2005

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Public Health

Major Professor

Raymond D. Harbison, Ph.D.

Committee Member

Ira S. Richards, Ph.D.

Committee Member

Philip P. Roets, Sc.D.

Committee Member

Skai W.Schwartz, Ph.D.

Keywords

Poly(adp-ribose)polymerase, Nicotinamide, 6(5H)-phenanthridone, Bromobenzene, Hepatotoxicity

Abstract

Previous studies have shown extensive cellular damage can activate poly(ADP-ribose) polymerase-1 (PARP-1) and cause a rapid decrease in the levels of NAD+ and ATP, thereby preventing apoptosis and promoting necrosis and inflammation. The purpose of this study was to extend previous observations that inhibitors of PARP-1 could alter acetaminophen and carbon tetrachloride-induced hepatotoxicity. Bromobenzene (BB) a glutathione dependent hepatotoxicant was tested. Groups of male mice were treated with a single dosage of 112mg/kg (0.075 ml/kg) BB by the intraperitoneal (ip) route. All animals were maintained in a controlled environment and provided food and water ad libitum. This dosage of BB resulted in hepatotoxicity as measured by an increase in serum alanine transferase (ALT). BB treatment resulted in a 5-fold increase in ALT. Moderate hepatotoxicity was detected with this treatment regime. Subsequently, another group of mice were treated with three treatments of nicotinamide at 0.5, 1 and 2 hours following BB treatment. Serum ALT elevations were reduced by 90% at 24 hours following BB and nicotinamide treatments. BB-induced liver pathology was also blocked by nicotinamide. Mortality among BB treated animals was also significantly ireduced by nicotinamide treatment. Mortality among mice treated with BB and nicotinamide was near control. The model was verified with a more potent and specific inhibitor, Phen. BB treatment was keep at the same level as in the previous study, and Phen was administered concomitantly. Serum ALT elevations were reduced by 75%. Phen also blocked BB-induced liver pathology. Mortality among mice treated with BB and Phen was reduced 75%. PARP-1 inhibitors appear to alter chemical-induced hepatotoxicity that has either a glutathione dependent or independent mechanism. PARP1 inhibitors may have pharmacological application for modifying chemical-induced liver injury.

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