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1.  A New Paradigm: Manganese Superoxide Dismutase Influences the Production of H2O2 in Cells and Thereby Their Biological State 
Free radical biology & medicine  2006;41(8):1338-1350.
The principal source of hydrogen peroxide in mitochondria is thought to be from the dismutation of superoxide via the enzyme manganese superoxide dismutase (MnSOD). However, the nature of the effect of SOD on the cellular production of H2O2 is not widely appreciated. The current paradigm is that the presence of SOD results in a lower level of H2O2 because it would prevent the non-enzymatic reactions of superoxide that form H2O2. The goal of this work was to: a) demonstrate that SOD can increase the flux of H2O2, and b) use kinetic modelling to determine what kinetic and thermodynamic conditions result in SOD increasing the flux of H2O2. We examined two biological sources of superoxide production (xanthine oxidase and coenzyme Q semiquinone, CoQ•−) that have different thermodynamic and kinetic properties. We found that SOD could change the rate of formation of H2O2 in cases where equilibrium-specific reactions form superoxide with an equilibrium constant (K) less than 1. An example is the formation of superoxide in the electron transport chain (ETC) of the mitochondria by the reaction of ubisemiquinone radical with dioxygen. We measured the rate of release of H2O2 into culture medium from cells with differing levels of MnSOD. We found that the higher the level of SOD, the greater the rate of accumulation of H2O2. Results with kinetic modelling were consistent with this observation; the steady-state level of H2O2 increases if K < 1, for example CoQ•− + O2 → CoQ + O2•−. However, when K > 1, e.g. xanthine oxidase forming O2•−, SOD does not affect the steady state-level of H2O2. Thus, the current paradigm that SOD will lower the flux of H2O2 does not hold for the ETC. These observations indicate that MnSOD contributes to the flux of H2O2 in cells and thereby is involved in establishing the cellular redox environment and thus the biological state of the cell.
doi:10.1016/j.freeradbiomed.2006.07.015
PMCID: PMC2443724  PMID: 17015180
superoxide dismutase; mitochondria; coenzyme Q; hydrogen peroxide; superoxide; free radical; redox environment
2.  The rate of cellular hydrogen peroxide removal shows dependency on GSH: Mathematical insight into in vivo H2O2 and GPx concentrations* 
Free radical research  2007;41(11):1201-1211.
Although its concentration is generally not known, glutathione peroxidase-1 (GPx-1) is a key enzyme in the removal of hydrogen peroxide (H2O2) in biological systems. Extrapolating from kinetic results obtained in vitro using dilute, homogenous buffered solutions, it is generally accepted that the rate of elimination of H2O2 in vivo by GPx is independent of glutathione concentration [GSH]. To examine this doctrine, a mathematical analysis of a kinetic model for the removal of H2O2 by GPx was undertaken to determine how the reaction species (H2O2, GSH, and GPx-1) influence the rate of removal of H2O2. Using both the traditional kinetic rate law approximation (classical model) and the generalized kinetic expression, the results show that the rate of removal of H2O2 increases with initial [GPxr], as expected, but is a function of both [GPxr] and [GSH] when the initial [GPxr] is less than [H2O2]. This simulation is supported by the biological observations of Li et al. (Cancer Res 60:3987-3939; 2000). Using genetically altered human glioma cells in in vitro cell culture and in an in vivo tumor model, they inferred that the rate of removal of H2O2 was a direct function of GPx activity × [GSH] (effective GPx activity). The predicted cellular average [GPxr] and [H2O2] for their study are approximately [GPxr] ≤ 1 μM and [H2O2] ≈ 5 μM based on available rate constants and an estimation of [GSH]. It was also found that results from the accepted kinetic rate law approximation significantly deviated from those obtained from the more generalized model in many cases that may be of physiological importance.
doi:10.1080/10715760701625075
PMCID: PMC2268624  PMID: 17886026
glutathione; glutathione peroxidase; hydrogen peroxide; mathematical modeling; kinetics
3.  The rate of cellular hydrogen peroxide removal shows dependency on GSH: Mathematical insight into in vivo H2O2 and GPx concentrations 
Free Radical Research  2007;41(11):1201-1211.
Although its concentration is generally not known, glutathione peroxidase-1 (GPx-1) is a key enzyme in the removal of hydrogen peroxide (H2O2) in biological systems. Extrapolating from kinetic results obtained in vitro using dilute, homogenous buffered solutions, it is generally accepted that the rate of elimination of H2O2 in vivo by GPx is independent of glutathione concentration (GSH). To examine this doctrine, a mathematical analysis of a kinetic model for the removal of H2O2 by GPx was undertaken to determine how the reaction species (H2O2, GSH, and GPx-1) influence the rate of removal of H2O2. Using both the traditional kinetic rate law approximation (classical model) and the generalized kinetic expression, the results show that the rate of removal of H2O2 increases with initial GPxr, as expected, but is a function of both GPxr and GSH when the initial GPxr is less than H2O2. This simulation is supported by the biological observations of Li et al.. Using genetically altered human glioma cells in in vitro cell culture and in an in vivo tumour model, they inferred that the rate of removal of H2O2 was a direct function of GPx activity × GSH (effective GPx activity). The predicted cellular average GPxr and H2O2 for their study are approximately GPxr ≤ 1 μm and H2O2 ≈ 5 μm based on available rate constants and an estimation of GSH. It was also found that results from the accepted kinetic rate law approximation significantly deviated from those obtained from the more generalized model in many cases that may be of physiological importance.
doi:10.1080/10715760701625075
PMCID: PMC2268624  PMID: 17886026
Glutathione; glutathione peroxidase; hydrogen peroxide; mathematical modelling; kinetics
4.  A controlled study of diet in patients with gout. 
Annals of the Rheumatic Diseases  1983;42(2):123-127.
To determine whether patients with gout have a diet which is distinctive in quality or quantity a careful dietary questionnaire was posed over 7 days to 61 men with gout and 52 control subjects. The average daily intake of most nutrients, including total purine nitrogen, was similar except that the patients with gout drank significantly more alcohol. Beer was the most popular beverage, and 25 (41%) of those with gout consumed more than 60 g alcohol daily (equivalent to 2 . 5 litres of beer). The heavy drinkers had a significantly higher intake of purine nitrogen, half of which was derived from beer. Though the effect of ingested purine on the blood uric acid is difficult to estimate, it probably was sufficient to have a clinical effect, augmenting the hyperuricaemic effect of alcohol itself.
PMCID: PMC1001083  PMID: 6847259
6.  Allopurinol treatment and its effect on renal function in gout: a controlled study. 
Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.
PMCID: PMC1000865  PMID: 7039523
7.  Tienilic acid: a single treatment for hyperuricaemia and hypertension? 
Annals of the Rheumatic Diseases  1980;39(4):373-376.
Tienilic acid is a drug with established uricosuric and hypotensive properties. We have examined its potential role as a single treatment for hyperuricaemia and hypertension, 2 disorders which are commonly associated. In 17 subjects with gout, blood uric acid levels were reduced by approximately 50%. Eleven of these patients also had hypertension which was improved by tienilic acid. However, a statistically significant effect was observed only with standing diastolic blood pressure. Side effects included acute episodes of gout in 4 patients and transient loin pain and dysuria in 1 patient. The precipitation of gouty arthritis is an acknowledged risk of all potent hypouricaemic drugs. The hazard of urate deposition in the renal tract implicit in the history of loin pain is a more serious complication. Thus, it would appear that tienilic acid is a potentially valuable drug which may have a special role in patients with hyperuricaemia and hypertension. Further study is necessary to determine how it may be best administered without the risk of renal damage.
PMCID: PMC1000559  PMID: 7436564

Results 1-7 (7)