AMP deaminase (AMPD) is an enzyme catalyzing the hydrolytic deamination of AMP and converts it to IMP, and plays an important role in purine matabolism in all eukaryotic cells. In human, two types of hereditary AMPD deficiency have been reported. Muscle AMPD deficiency is found in individuals with metabolic myopathy, while AMPD deficiency in red blood cells is found in asymptomatic individuals. Advances of molecular study in the last decade have revealed multiple gene family encoding AMPD peptides. First, three AMPD genes have been isolated and characterized in humans and rodents. Second, molecuar basis of AMPD deficiency in skeletal muscle and red blood cells has been identified. Regulatory mechanisms on AMPD genes and the relationship between gene regulation and AMPD deficiencies have been also studied. In addition, molecular and subcellular functions of AMPD are being studied. Further studies will clarify new functional aspects of AMPD including interaction to other molecules.
The effect of exhaustive treadmill running exercise on purine nucleotide degradation was examined, in both slow-twitch and fast-twitch muscle fibers in rats. Rats were divided into three groups: resting control groups without allopurinol administration (n = 5) and with allopurinol administration (n=24), and an exercise group with allopurinol administration (n=48). Purine metabolites were assayed by high performance liquid chromatography at 0,30,60,120,180, and 300 min after exercise. Plasma uric acid concentration was suppressed by allopurinol in both the exercise and control groups. There was a significant increase in plasma inosine concentration immediately after exercise, which returned to basal levels within 30 min of recovery. Plasma hypoxanthine and xanthine concentrations increased immediately after the exhaustive exercise, and remained significantly higher than resting controls until 60 and 300 min of the recovery phase, respectively. In extensor digitorum longus muscle, the content of adenosine 5'-triphosphate decreased, but inosine 5'-monophosphate and inosine increased immediately after exercise. Hypoxanthine level in extensor digitorum longus muscle was increased following exercise, and this remained higher than resting controls at 120 min of recovery. Decreased adenosine 5'-triphosphate content in soleus muscle was observed immediately after exercise. Although inosine 5'-monophosphate in soleus muscle did not show a significant change, inosine content was elevated immediately after exercise. Significant increases in hypoxanthine levels were observed from 0 to 60 min of the recovery phase. It was found that hypoxanthine levels in soleus muscle and extensor digitorum longus muscle increased to about the same degree. These results suggest that adenine nucleotide degradation and the subsequent formation of uric acid precursors occurred continuously during and following exhaustive exercise, in slow-twitch muscle fibers as well as fast-twitch muscle fibers, which may later on result in exercise-induced prolonged hyperuricemia.
IMP dehydrogenase catalyzes the rate-limiting reaction of de novo guanylate biosynthesis. Changes in IMP dehydrogenase activity have been implicated in the regulation of cell growth and differentiation. However, synthesis of guanine nucleotides is reported to be reduced by other differentiation inducers during cell maturation. We investigated here, the relationship between low intracellular GTP levels and differentiation induction using IMP dehydrogenase inhibitors including mycophenolic acid and mizoribine or all- trans retinoic acid. Treatment with IMP dehydrogenase inhibitors or all- trans retinoic acid induced morphologic, antigenic, and enzymatic differentiation in HL-60 and U937 cells. However, changes in intracellular GTP levels differed in each agent. The addition of mycophenolic acid resulted in a rapid decrease in intracellular GTP levels to 20-30% of control values which were then maintained at the lowest level during the culture period. Treatment with mizoribine decreased intracellular GTP levels to approximately 20-30% of controls for less than 24 h, then the GTP levels recovered to 50-60% and were maintained at that level. On the other hand, treatment with alltrans retinoic acid gradually decreased the intracellular GTP levels to approximately 80% of control values and induced maturation. Concurrent addition of guanosine abrogated IMP dehydrogenase inhibitors-induced differentiation, whereas all- trans retinoic acid-induced maturation was found to be independent of exogenous guanosine. Exposure to IMP dehydrogenase inhibitors for short period of time such as 24 h resulted in induction, whereas treatment for less than 12 h did not induce maturation. GTP levels reduced to approximately 20-30% of control for at least 24 h as a result of IMP dehydrogenase inhibitors may induce maturation, suggesting that differentiation induction by IMP dehydrogenase inhibitors differs from that by all-trans retinoic acid regarding intracellular GTP metabolism.
We conducted a prospective cohort study to clarify the effect of the change in serum uric acid levels (SUA) on mortality among 12,017male workers aged 40 to 55 years. Baseline data were collected 2 times at 5 year intervals, during health examinations. Vital status was followed after the second visit, and the average observation period was 4.2 years. Subjects were divided into 3 groups according to the change in SUA, ascended, unchanged, and descended. A positive association was observed between SUA change and mortality. The relative risk (RR) was 0.92,1.0,1.10and 2.09, in the groups SUA 1-1.9mg/dl descended, unchanged,1-1.9mg/dl ascended and over 2 mg/dl ascended, respectively. When SUA descended by over 2 mg/dl, RR was 1.32. When we analyzed the subjects by the SUA of the first visit, RR increased when SUA ascended by over 2 mg/dl, even in the group whose first SUA was under 6.4mg/dl. RR was 21.3 (p<0.01), when SUA ascended by over 1 mg/dl in the group whose first SUA level was over 8.5mg/dl.
To elucidate the findings of patients with gout or hyperuricemia, the results of a questionnaire-based case control study on life style and health ware investigated. Responses from 1,025 patients in 74 hospitals were analyzed. As expected, patients with gout or hyperuricemia had higher type A scores, but more prominently, exhibited many factors which can increase serum uric acid levels, than other disease-control patients. This tendency was marked in patients living in urban areas. Thus, urban life styles may increase the risk of hyperuricemia and gout via the accumulation of physical stress. This knowledge may be useful for non-pharmacological control of patients with gout or hyperuricemia.