Semester

Summer

Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

Davis College of Agriculture, Natural Resources and Design

Department

Animal and Nutritional Sciences

Committee Chair

Hillar Klandorf

Committee Co-Chair

Kenneth Blemings

Committee Member

Melissa Marra

Committee Member

Janet Tou

Committee Member

Knox VanDyke

Abstract

Birds have a remarkable longevity for their body size despite an increased body temperature, higher metabolic rate, and increased blood glucose concentrations. Theoretically, birds should sustain a much higher degree of oxidative damage yet do not, in part due to the powerful antioxidant, uric acid. As the end-product of purine degradation, uric acid is generated in the xanthine/hypoxanthine reactions catalyzed by xanthine oxiodreductase (XOR). In the first study, inosine, a purine precursor, was fed to 3 groups of 5 birds: Group 1 was fed 0 (control), Group 2, 0.6 mols inosine/kg feed (INO) and Group 3, INO treatment plus 50 mg allopurinol/kg BM (INOAL). Allopurinol is a known inhibitor of XOR and thereby reduces uric acid (UA). INOAL birds showed lower total liver XOR activity (p=0.005) but kidney XOR activity was not affected. Both INO and INOAL birds had higher plasma and kidney UA concentrations than controls. Liver uric acid (LUA) was significantly reduced in INOAL birds when compared to other treatments. XOR gene expression was increased (p=0.007) in the liver tissue of INOAL birds when compared to CON and INO birds. However, there were no significant changes in XOR gene expression in the kidney tissue. To our knowledge, this is the first report of XOR gene expression measured under these conditions. The results suggest that regulation of UA production is tissue dependent. The results also indicate a compensatory effect of allopurinol on XOR gene expression which can be linked to a decrease in antioxidant protection from UA.;In the second study, Cobb x Cobb broilers (n=12; 4 weeks old) were separated into two treatments (n=6); control (CON) and AL (allopurinol 35mg/kg BW). The purpose of this study was to assess mitochondrial function in broiler chickens in response to potential oxidative stress generated from the administration of allopurinol. Mitochondria were freshly isolated from liver tissue and assessed for State III and State IV respiration using polarography. There was a significant reduction in State III respiration (p=0.01) and State IV respiration (p=0.007) in allopurinol-treated birds compared to the controls. The purpose of the third study was to assess the effect of allopurinol on gene expression of inflammatory cytokines IFN-gamma;, IL-1beta;, IL-6 and IL-12p35 as well as iNOS and XOR in liver tissue. Cobb x Cobb broilers were separated into two groups at 4 weeks of age (n=10); control (CON) and ALLO (allopurinol 35mg/kg BW). After one week of allopurinol treatment, half of the birds in each group (CON 1 and ALLO 1) were euthanized with the remaining continued with allopurinol treatment for an additional week (CON 2 and ALLO 2). Results demonstrated a significant increase in gene expression of XOR, IFN-gamma;, IL-1beta;, and IL-12p35 in ALLO 2 birds as compared to birds in CON 2. iNOS was numerically increased in ALLO 2 birds though this was not significant (p=0.076). Liver uric acid content was significantly decreased in both ALLO 1(p=0.003) and ALLO 2 (p=0.012) birds when compared to CON1 and CON 2 respectively. No differences in body weight (BW) were measured from 0-7 days of age in any of the groups. However there was a significant decrease in BW of AL2 birds when compared to CON 2 birds at 10 (p= 0.011) and 14 days (p=0.012) of treatment. The reduced uric acid concentration in the liver suggests that allopurinol treatment leads to a lowered antioxidant activity in this tissue which increases inflammation and oxidative stress and results in mitochondrial dysfunction.

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