Phenytoin-Folate Interactions: Differing Effects of the Sodium Salt and the Free Acid of Phenytoin

Chronic phenytoin (PHT) treatment has long been associated with folate deficiency. It has been suggested that pH changes in the gut associated with PHT ingestion may be responsible for decreased folate uptake either by direct inhibition of folate transport into the intestinal mucosa or by inhibition of folate conjugase activity. To examine these possibilities, rats were gavaged chronically with PHT using either the sodium salt (NaPHT) or the free acid (HPHT) in the presence of folic acid as the dietary source of folate. The NaPHT caused a greater depletion of folate in the liver and brain and a significant increase in methylenetetrahydrofolate reductase activity in the liver. The HPHT caused a significantly decreased weight gain over the 8 weeks of treatment and resulted in a much higher liver PHT concentration and a slightly lower plasma PHT concentration. These data support the hypothesis that PHT-induced changes in pH in the gut affect the enterohepatic circulation of folate.     

Ginkgo biloba modulates glutathione redox cycle in vascular endothelial cells

We recently reported that Ginkgo biloba extract (GBE) suppressed oxidative burst in macrophages and protected bovine pulmonary artery endothelial cells (PAEC) from oxidant injury. In this study the effects of GBE on glutathione (GSH) redox cycle and activity of antioxidant enzymes were investigated. Confluent monolayers of PAEC were incubated with GBE for 8–48 h, washed, and then lysed with Triton X-100. Biochemical assays were performed with the lysate. GBE caused both dose- and time-dependent increase in GSH level and glutathione disulfide (GSSG) reductase activity while GSH peroxidase and superoxide dismutase activity remained unaffected. Exposure of PAEC to an organic oxidant tert-butyl hydroperoxide (tBHP) resulted in decreased GSH level, increased lipid peroxidation, and elevated leakage of intracellular lactate dehydrogenase. Preincubation or simultaneous treatment of PAEC with GBE prevented these changes induced by tBHP. Our data suggest that the antioxidant effect of GBE may be due to its modulation of the GSH redox cycle in PAEC as well as direct scavenging of the oxidant.     

冠心病患者甲基四氢叶酸还原酶基因多态性的研究

目的 :探讨同型半胱氨酸(HCY)代谢相关酶甲基四氢叶酸还原酶 (MTHFR)基因多态性、血浆HCY、叶酸、维生素B12 水平与冠心病的关系。方法:用酶联免疫试剂盒测定血浆HCY ,放射免疫法测定维生素B12 和叶酸水平 ,以多聚酶链反应 -限制性内切酶片段长度多态性 (PCR -RFLP)分析MTHFRC677T基因型。结果:冠心病组MTHRR基因TT型、TC型及CC型频率分布及T、C等位基因频率与对照组无显著差异 (χ2=1.427,P>0.05;χ2=1.257,P>0.05)。冠心病组HCY水平为 (21.58±12.69)umol/L显著高于对照组(P<0.01)。叶酸浓度平均(2.78±1.66)ng/ml,维生素B 12 浓度平均 (231.76±143.78) pg/ml,明显低于对照组 (P<0.01)。冠心病组中3种基因型的HCY水平有显著差异 ,TT型HCY明显高于CC型 (P<0.05)。结论:高HCY血症是冠心病发病的危险因素 ,血浆HCY水平的升高与叶酸、维生素B12 的降低有关。MTHFR基因C677T的TT突变是高同型半胱氨酸血症的原因 ,但MTHFRC677T基因多态性与冠心病的发生无显著相关     

Inhibition of rat folic acid reductase activity by trimethoprim during the later stages of gestation

Summary The increased level of folic acid reductase activity in rats during the perinatal period is inhibited following the oral administration of 5 or 50 mg/kg Trimethoprim. When the enzyme activity was tested in vitro, the highest sensitivity to the antimetabolite was displayed by the liver reductase isolated from rats the 20th day of pregnancy, the lowest was observed in the foetal liver extract.It is proposed that the stimulated reductase activity during the pregnancy is caused by a newly synthesized, Trimethoprim-sensitive enzyme form. The results of the in vitro experiments could contribute to the suggested hypothesis.     

亚甲基四氢叶酸还原酶基因多态性与儿童支气管哮喘的相关性

目的探讨儿童支气管哮喘与亚甲基四氢叶酸还原酶（MTHFR）基因C677位点C→T多态性的关系.方法采用PCR和限制性内切酶片段长度多态性的方法对113例儿童支气管哮喘和131例健康儿童的MTHFR基因第677位点基因多态性进行研究.结果儿童支气管哮喘患者与对照组等位基因比较差异有显著性（x^2=6.69,P＜0.05）.CC、CT、TT3种基因型之间差异存在显著性（x^2=6.35,P＜0.05）.结论MTHFR C677位点C→T的基因突变可能与儿童支气管哮喘的发生有关.     

Effect of halothane on the hepatic drug metabolizing system

Summary Pretreatment with 2 Vol.-% halothane in oxygen for 1 h once daily on 5 days significantly decreased the hexobarbital sleeping time by about 49%. The activity of the NADPH-cytochrome c reductase was increased by 33%, whereas the amount of cytochrome P₄₅₀ was not altered.A prolongation of the daily halothane exposure to 2 h increased the activity of the NADPH-cytochrome c reductase by about 60%.     

Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy?

Fluorouracil (5-FU) is widely used in the treatment of colorectal cancer. Methylenetetrahydrofolate reductase (MTHFR) may play a central role in the action of 5-FU, an inhibitor of thymidylate synthase, by converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The aim of this study was to ascertain whether two polymorphisms in the MTHFR gene (677C>T and 1298 A>C) could be used as genomic predictors of clinical response to fluoropyrimidine-based chemotherapy (in combination with irinotecan or oxaliplatin). Ninety-four patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-containing chemotherapy as a first line treatment were studied. The results suggest that the MTHFR genotype cannot be considered as an independent factor of outcome in colorectal cancer patients under 5-FU-based chemotherapy.     

MTHFR Polymorphism and Bone Mineral Density: Meta-Analysis of Published Studies

The C677T (rs1801133) polymorphism of methylenetetrahydrofolate reductase (MTHFR) has been associated with bone status in some studies, but the results have been mixed. In order to have a better understanding of this issue, we performed a meta-analysis of studies about the association of the C677T polymorphism and bone mineral density (BMD). Eight studies analyzed the relationship with spine BMD. When their results were combined, individuals with TT genotype showed a small but significantly reduced BMD compared to those with TC and CC genotypes. The weighted mean difference (WMD) was 18.0 mg/cm² (P = 0.001, 95% confidence interval [CI] 7.1–28.9), without statistical evidence for between-study heterogeneity (P = 0.28, I² = 17%). Six studies analyzed femoral neck BMD. A test for heterogeneity was significant (P = 0.03, I² = 56%). Individuals with TT alleles tended to have somewhat lower BMD, but the difference was not statistically significant. In random effects model, the WMD between the TT and TC/CC genotypes was 6.4 mg/cm² (95% CI –7.8 to 21.2, P = 0.36). Total hip BMD was measured in four studies. They showed a significantly lower BMD in subjects with TT alleles: WMD 19.7 (95% CI 5.3-34.1) mg/cm², P = 0.007, in comparison with TC/CC subjects. When we considered only studies on women, the WMD in BMD between TT and TC/CC genotypes was significant at the spine (22.1 mg/cm², 95% CI 8.6-35.6; P = 0.001) and the femoral neck (15.5 mg/cm², 95% CI 4.3-26.7; P = 0.007). There was no evidence for heterogeneity. The small number of studies did not allow a meaningful sex-stratified analysis of total hip BMD or a separate analysis of male data. In conclusion, the C677T polymorphism of the MTHFR gene is associated with small differences in BMD, at least in women.     

Thrombophilic screening in young patients (< 40 years) with idiopathic ischemic stroke: a controlled study

Introduction

Despite extensive clinical and laboratory investigations, the etiology of ischemic stroke remains unknown in approximately one third of patients.

Materials and Methods

Thirty-four consecutive patients less than 40 years old (Males 13, Females 21, mean age 26.6 years, range 2-39) with documented ischemic stroke underwent, one year after the acute event, laboratory evaluation of antithrombin, protein C, free and total protein S, activated protein C resistance, fibrinogen, factor VII:C, homocysteine levels and antiphospholipid antibodies (APA). Moreover, prevalence of F5 R506Q, F2 G2021A and homozygosis for thermolabile variant C677T of the methylenetetrahydrofolate reductase (MTHFR) were also evaluated and compared to the results obtained in 120 normal controls.

Results

Antithrombin and protein C levels resulted normal in all cases. One patient (2.9%) showed free protein S deficiency and 3 patients (8.8%) had activated protein C resistance. Homocysteine levels above 15 μmol/L were found in one patient (2.9%). APA were found in 21 patients (61.7%) and in only 2 out of 120 (1.66%) controls (OR = 95.31; 95% C.I.: 18.22-667.81). The multivariate analysis selected that the presence of APA was significantly associated with an increased risk of stroke (OR = 156.60; 95% C.I.: 25.99-943.47) in this cohort of patients. The combination between APA and cardiovascular risk factors determined a risk of 29-fold (OR = 29.31; 95% CI: 3.28-261.69).

Discussion

Our data suggest that the presence of APA is associated with an increased risk of idiopathic ischemic stroke in young patients. Furthermore, also the combination of APA and cardiovascular risk factors is significantly associated with development of idiopathic ischemic stroke.