Effects of allopurinol on uric acid concentrations, xanthine oxidoreductase activity and oxidative stress in broiler chickens

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Abstract

The purpose of this study was to determine the effects of allopurinol (AL) on xanthine oxidoreductase (XOR) activity and uric acid (UA) levels in chickens. Thirty 5-week-old broilers were divided into three groups and fed 0 (control), 25 (AL25) or 50 (AL50) mg AL per kg of body mass for 5 weeks. Chicks were weighed twice weekly and leukocyte oxidative activity (LOA) and plasma purine levels were determined weekly in five birds per group. Chicks were sacrificed after 2 or 5 weeks, and samples from tissues were taken for analysis of XOR activity. Plasma UA concentrations were lower (P < 0.001) and xanthine and hypoxanthine concentrations were greater (P < 0.001) in AL25 and AL50 birds compared to controls, whereas no differences (P = 0.904) were detected in allantoin concentrations. By week 5, body mass was reduced (P < 0.001) to 84.0 and 65.1% of that in controls for AL25 and AL50 broilers, respectively, and LOA was 4.1 times greater (P < 0.05) in AL25 compared to control birds. Liver XOR activity was increased by 1.1 and 1.2 times in AL25 and AL50 birds, but there was no change (P > 0.05) in XOR activity in the pancreas and intestine. These results suggest that AL effect on XOR activity is tissue dependent.

Introduction

Birds have remarkable longevity for their body size despite the fact that they also have higher metabolic rates, body temperatures and blood glucose concentrations as compared to mammals (Constantini, 2008). Theoretically, birds should sustain proportionately greater damage from processes such as the production of oxygen reactive species (ROS), which are involved in the physiological deterioration that causes aging (Monnier et al., 1991, Yu, 1996). However, birds have a lower rate of heart, brain, kidney and lung mitochondrial ROS production relative to mammals of comparable body size (Constantini, 2008), which suggests that they have developed adaptations for preventing age-related tissue damage caused by ROS and advanced glycosylation endproducts (Holmes et al., 2001). Birds, as well as other long-lived species including humans, reptiles and higher order primates, have increased plasma levels of uric acid (UA) compared to most mammals. UA functions as a protective agent against oxidative stress and limits the tissue damage associated with ROS production (Holmes and Austad, 1995, Klandorf et al., 1999, Klandorf et al., 2001). It has been speculated that the high levels of UA in birds contribute significantly to their relatively long life span compared to mammals (Holmes et al., 2001).

UA is produced by the enzyme xanthine oxidoreductase (XOR) from xanthine and hypoxanthine, which in turn are produced by the breakdown of purines. The XOR exists in two distinct functional but interconvertible forms: xanthine oxidase (XO; EC 1.1.3.22) and xanthine dehydrogenase (XD; EC 1.1.1.204). XOR contributes to the antioxidant defenses of the organism by forming UA, but it has also been reported that XOR can act as a source of superoxide and hydrogen peroxide, and its role as a causative factor in ischemia/reperfusion damage in human tissues is well documented (Chung et al., 1997, Harrison, 2002). Allopurinol (AL) is a potent inhibitor of XOR which has been widely used for treatment of gout and hyperuricemia in humans. In birds, AL has also been shown to reduce plasma UA levels (Simoyi et al., 2002, Klandorf et al., 2001), but its effects on XOR activity and oxidative stress have not been extensively investigated. Lee and Fisher (1972) reported that chickens administered AL (750 mg/kg feed) from hatch to 28 days of age showed no adverse effects except a slight reduction in body mass (BM). In contrast, Klandorf et al. (2001) observed that BM was decreased by 41% and mortality was increased from 7 to 40% in broilers fed AL (10 mg/kg BM) from 12 to 22 weeks of age compared to control birds. Woodward et al. (1972) and Lee and Fisher (1972) reported that AL feeding increased XOR activity in the liver of chicks but had no effects on the pancreas, suggesting that AL effects may be tissue specific. However, there have been no further studies that have investigated this hypothesis in birds, although a variable response of different tissues to AL administration has been reported in the mouse (Lee, 1973). The objective of this study was to determine if XOR activity in chickens is differently regulated under conditions where concentrations of UA are decreased by AL.

Section snippets

Broilers and experimental procedure

Eighty day old broiler chicks (Gallus gallus domesticus; Ross × Cobb, mixed sex) were obtained from a local hatchery (Pilgrim Farms, Moorefield, WV) and maintained under standard husbandry practices. Chicks were floor reared and fed ad libitum in pan feeders. A starter diet was fed for 3 weeks and then changed to a standard grower diet. Recommendations for space, temperature, light, and husbandry were followed (Aviagen, 2009), and the experimental protocol was approved by the West Virginia

Results

As shown in Table 1, the treatment with AL decreased (P < 0.001) BM and BM gain, and interactions AL ×  time (P < 0.001) were observed for these variables. After 5 weeks of AL feeding, BM was reduced to 84.0 and 65.1% of that in control group for AL25 and AL50 broilers, respectively. Feed intake (results not shown) was reduced by AL feeding, with mean daily values of 338, 241 and 182 g feed per bird for CON, AL25 and AL50, respectively, over the last week of the experiment.

LOA was measured as an

Discussion

The effects of AL on animal growth rate reported in the literature are controversial. Lee and Fisher (1972) fed AL (750 mg/kg feed) to chicks from hatch to 28 days of age and observed no adverse effects, with the exception of a slight reduction in BM. In contrast, Klandorf et al. (2001) administered low doses of AL (10 mg/kg BM) to broilers from 12 to 22 weeks of age and observed that AL-treated chicks had significantly lower BM (62%) and increased mortality (7% vs. 40%) compared to controls. The

Acknowledgements

This work was supported by Hatch grant (H393) and a grant from the Dr. Joe. C. Jackson College of Graduate Studies and Research at the University of Central Oklahoma. M. D. Carro gratefully acknowledges the support from the Spanish Ministerio de Ciencia e Innovación (PR2008-0025) and thanks Dr. Antonio J. Molina for his helpful advice on the analysis of xanthine oxidase and dehydrogenase activities. Chicks were a generous gift from Pilgrims Pride, Moorefield, WV. Thanks are given to the West

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