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Dose adjustment based on the developmental changes of drug metabolic enzyme activity and their pharmacological activity.

根据药物代谢酶活性及其药理活性的发育变化调整剂量。

基本信息

批准号：
23790212
负责人：
TAYAMA Yoshitaka
金额：
$ 2.75万
依托单位：
Hiroshima International University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

项目摘要

In the present study, we observed the developmental changes of aldehyde oxidase (AO) and xanthine oxidase (XO) in postnatal rat liver. The expression of AO was closely correlated with the oxidase activity. As for XO, there was good relation to the expression of XO, as like AO. It is said that AO and XO contain molybdenum (Mo) in their active center, and then Mo cofactor effect on the activity. We evaluated the developmental changes of Mo cofactor Synthesis (MOCS) protein. There is the developmental change on MOCS protein, and we observed the good relation to AO and XO activity. Thus, the AO and XO activity are regulated by both the expression of the enzyme and MOCS protein. Allopurinol is metabolized to oxypurinol, a potent XO inhibitor, by AO and XO. We examined the change of allopurinol metabolism and their efficacy by the developmental changes. Allopurinol efficacy is evaluated as the XO inhibition. The level of XO activity was predicted from the ratio of xanthine and hypoxanthine in the cytosols, calculated according to the following equation: Ratio of xanthine formation (RX) = [(xanthine/ (xanthine + hypoxanthine)]Three weeks aged rats have lower allopurinol oxidase activity than 6 weeks aged rats (3 weeks: 1.69nmol /60 min/mg protein, 6 weeks: 8.93 nmol /60 min/mg protein). The level of RX, the index of XO activity, in 3 weeks rats was higher than that in 6 weeks rats (3 weeks: 0.76, 6 weeks: 0.56). The allopurinol efficacy, XO inhibition, was increased with age. We evaluated the contribution of allopurinol metabolism by AO and XO. AO metabolite 18.0% of allopurinol in 3 weeks aged rats. On the other hand, AO metabolite 80.7% in 6 weeks aged rats. It was observed that the contribution by AO on allopurinol metabolism changes with age.

本文观察了生后大鼠肝脏中醛氧化酶(AO)和黄嘌呤氧化酶(XO)的发育性变化。AO的表达与氧化酶活性密切相关。至于XO，与AO一样，与XO的表达有很好的相关性。一般认为，AO和XO的活性中心含有钼，而钼是影响活性的重要因素。我们评价了钼辅助因子合成(MOCS)蛋白的发育变化。Mocs蛋白有发育性变化，并与AO和XO活性有良好的相关性。因此，AO和XO的活性受酶和MOCS蛋白表达的调节。别嘌醇被AO和XO代谢成一种有效的XO抑制剂--氧嘌醇。我们通过发育变化来检测别嘌醇代谢的变化及其疗效。别嘌醇的疗效评价为对XO的抑制。根据黄嘌呤/次黄嘌呤的比值预测XO活性水平，计算公式如下：黄嘌呤形成比(RX)=[(黄嘌呤/(黄嘌呤+次黄嘌呤)]]3周龄大鼠的别嘌醇氧化酶活性低于6周龄大鼠(3周龄：1.69nmol/60min/mg蛋白，6周龄：8.93nmol/60min/mg蛋白)。XO活性指标Rx水平3周高于6周(3周：0.76，6周：0.56)。别嘌醇对XO的抑制作用随着年龄的增长而增加。我们评估了AO和XO对别嘌醇代谢的贡献。3周龄大鼠脑氧代谢产物别嘌醇含量为18.0%。而在6周龄的大鼠中，AO代谢物占80.7%。观察到，随着年龄的增长，AO对别嘌醇代谢的贡献也会发生变化。