Intestinal folic acid absorption and the acid microclimate

The effects of various substances and circumstances on folic acid absorption and surface pH were investigated in vitro in rat proximal jejunum. Prior consumption of alcohol adlibitum, phenytoin and in vitro methotrexate had no effect on folate absorption. In contrast, ethanol in vitro, low sodium ion containing buffers in vitro and oral methotrexate given prior to experiment reduced absorption. Folate absorption did not correlate with water movement since methotrexate decreased folate but enhanced fluid absorption, ruling out direct coupling. Surface pH was elevated by the low sodium ion containing buffers, ethanol in vitro and oral methotrexate, correlating inversely with folate absorption. The parallelisms between absorption and changes in surface pH support the microclimate hypothesis of folic acid absorption where the rate of transport is largely determined by the surface pH of the proximal jejunum.Part of this work was presented at the Biochemical Society, Cambridge Meeting, 1977. Biochem Soc Trans 6:297–299 (1978)     

Guanosine triphosphate cyclohydrolase in Plasmodium falciparum and other Plasmodium species

GTP cyclohydrolase (EC 3.5.4.16), the first enzyme in the pteridine pathway leading to the de novo formation of folic acid, has been identified and isolated from the human malaria parasite, Plasmodium falciparum. The enzyme was purified 200-fold by high performance size-exclusion chromatography on a TSK-G-3000 SW protein column. The molecular weight was estimated at 300 000. Optimal enzyme activity was observed at pH 8.0 and 42 degrees C. The Km for GTP was 54.6 microM. Products of the enzyme reaction were identified as the carbon-8 of GTP and D-erythro-dihydroneopterin triphosphate. ATP was a competitive inhibitor (Ki = 600 microM) of the enzyme. Activity of the enzyme was Mg2+-independent, whereas Mn2+, Cu2+ and Hg2+ (5 mM) were inhibitory. GTP cyclohydrolase activity was also identified in a murine parasite, Plasmodium berghei, and a simian parasite, Plasmodium knowlesi. Activity of the enzyme in P. knowlesi, an intrinsically synchronous quotidian parasite, was found to be dependent on the stage of parasite development.     

Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption

Hereditary folate malabsorption (HFM) is an autosomal recessive disorder, recently shown to be due to loss-of-function mutations of the proton-coupled folate transporter (PCFT-SLC46A1), resulting in systemic and central nervous system folate deficiency. Data is emerging on the spectrum of PCFT mutations associated with this disorder. In this report, novel mutations are described in three subjects with HFM: A335D/N68Kfs (c.1004C>A/c.204-205delCC), compound heterozygous mutations, and two homozygous PCFT mutations, G338R (c.1012G>C) and E9Gfs (c.17-18insC). Functional assessment of A335D and G338R PCFT mutants transfected into folate transporter-deficient HeLa R1-11 cells indicated a complete loss of transport activity. There were neurological deficiencies in two of the families reported; in particular, late-onset seizures. The importance of early diagnosis and treatment to achieve physiological cerebrospinal fluid folate levels is emphasized.     

肾病综合征患者血浆同型半胱氨酸和血清叶酸、维生素B12的含量变化及其临床意义

目的检测肾病综合征（PNS）患者血浆同型半胱氨酸（Hcy）和血清叶酸、维生素B12（VitB12）的变化并探讨其临床意义。方法采用高效液相色谱一荧光检测法测定PNS患者血清Hcy浓度,Access全自动微粒子发光仪测定其血清中的叶酸和VitB12含量。结果PNS患者血浆Hcy含量显著高于对照组,VitB12含量显著低于对照组,叶酸的含量与对照组比较差异无显著性。血浆Hcy浓度与内生肌酐清除率和24h尿蛋白排泄量有相关性。结论高Hcy和低VitB12参与PNS的发病过程,是PNS患者发生心血管功能紊乱的危险因素。     

Contribution of CSF analysis to the diagnosis of inborn errors of metabolism in adult patients

The diagnosis of certain metabolic diseases is problematic because it cannot be achieved with conventional blood and urine analyses but requires cerebrospinal fluid (CSF) study. CSF analysis is essential for the diagnosis of neurotransmitter metabolic disorders (synthesis defects of biogenic monoamines, non ketotic hyperglycinemia and homocarsinosis), defects of specific transporters (glucose cerebral transporter (Glut1) deficiency and cerebral folate deficiency) and is of help for the diagnosis of disorders of cerebral energy metabolism (respiratory chain disorders and pyruvate dehydrogenase deficiency). Our goal is to give an outline of hereditary metabolic diseases whose diagnosis is based on CSF analysis. We will detail late onset clinical forms which may be first seen in an adult neurology department.     

Cobalamin deficiency and related disorders in infancy and childhood

This review discusses recent knowledge of the many causes of cobalamin deficiency in infancy and childhood. These causes are classified as (1) inadequate intake, (2) inadequate absorption and (3) inadequate utilisation. It is emphasized that the serum B₁₂ may be normal in cases of the grossest derangement of B₁₂ metabolism, with extreme functional deficiency of this group of vitamins (the cobalamins). For completeness, causes of folate deficiency and other conditions causing megaloblastosis in children are also briefly outlined. Curriculum vitae. Professor David M. Matthews was born in 1926 in High Wycombe, England. He graduated in Medicine at the University of London in 1949, and joined the Department of Chemical Pathology of the Westminster Medical School, London, in 1965. In 1970 he was appointed head of the newly formed Department of Experimental Chemical Pathology at the Westminster Medical School. He has worked on cobalamin metabolism for many years, since 1966 in collaboration with Dr. J. C. Linnell. His other main research interest is in the intestinal absorption of peptides in man and animals. Curriculum vitae. John C. Linnell was born in 1934 in Strawberry Hill, Twickenham, England. He graduated in Physiology and Chemistry at the University of London in 1961 and received his Doctorate in Biochemistry in 1974. After some years in pharmaceutical research, he joined the Department of Chemical Pathology of the Westminster Medical School, London, in 1966 and since then has worked on cobalamin metabolism, developing a micromethod for estimation of coenzyme or other forms of cobalamin and investigation of inborn metabolic errors.     

Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment

Over the past decades, numerous reports have covered the crucial role of multidrug resistance (MDR) transporters in the efficacy of various chemotherapeutic drugs. Specific cell membrane-associated transporters mediate drug resistance by effluxing a wide spectrum of toxic agents. Although several excellent reviews have addressed general aspects of drug resistance, this current review aims to highlight implications for the efficacy of folate-based and other types of chemotherapeutic drugs. Folates are vitamins that are daily required for many biosynthetic processes. Folate supplementation in our diet may convey protective effects against several diseases, including cancers, but folate supplementation also makes up an essential part of several current cancer chemotherapeutic regimens. Traditionally, the folate leucovorin, for instance, is used to reduce antifolate toxicity in leukemia or to enhance the effect of the fluoropyrimidine 5-fluorouracil in some solid tumors. More recently, it has also been noted that folic acid has the ability to increase antitumor activity of several structurally unrelated regimens, such as alimta/pemetrexed and cisplatin. Moreover, studies from our laboratory demonstrated that folates could modulate the expression and activity of at least two members of the MDR transporters: MRP1/ABCC1, and the breast cancer resistance protein BCRP/ABCG2. Thus, folate supplementation may have differential effects on chemotherapy: (1) reduction of toxicity, (2) increase of antitumor activity, and (3) induction of MRP1 and BCRP associated cellular drug resistance. In this review the role of MDR proteins is discussed in further detail for each of these three items from the perspective to optimally exploit folate supplementation for enhanced chemotherapeutic efficacy of both antifolate-based chemotherapy and other classes of chemotherapeutic drugs.     

Acid folic and pregnancy: A mandatory supplementation

Neural tube defects (NTD) occur in 0.5 to 2 per 1000 pregnancies with various handicaps for the affected child. It is now well established that folic acid deficiency (absolute or relative) is a predisposing factor to this type of malformation. Several randomized controlled trials showed that high-dose folic acid (4 mg) is an essential factor for prevention of neural tube defects recurrence and significantly prevents the first occurrence of neural tube defects with a lower dose (0.4 mg). Other etiologies can favor the occurrence of NTD such as MTHFR polymorphism, some antiepileptic therapies, obesity and pregestational mellitus diabetes. Necessity of a preconception folic acid supplementation or at least folate nutritional status evaluation should be known for all of us including patients and public.     

The pharmacokinetics of reduced folates after intraperltoneal and intravenous administration of racemic [6S,R]-folinic acid

We investigated the pharmacokinetics of tetrahydrofolates following the administration of [6S,R]-folinic acid and 5-fluorouracil delivered i.v., i.p., and by a combination of both routes in patients with colon cancer. The concentrations of the biologically active tetrahydrofolates ([6S]-folinic acid and 5-methyltetrahydrofolate) and the relatively inert diastereomer [6R]-folinic acid were monitored using a selective on-line coupled achiral-chiral high-performance liquid chromatographic method. In plasma, a target concentration of 5 M active tetrahydrofolates, which is considered necessary for an optimal synergistic effect, could be achieved after i.v. or combined i.v. and i.p. administration but was not reached in a patient receiving i.p. [6S,R]-folinic acid alone. In three patients receiving i.p. [6S,R]-folinic acid a high level of [6S]-folinic acid was observed in ascites, suggesting that the peritoneal cavity may act as a storage site for tetrahydrofolates after i.p. administration. In these patients, only a trace level of the active metabolite 5-methyltetrahydrofolate was detected in ascites, which may indicate that tetrahydrofolate derivatives penetrate only minimally, if at all, into the peritoneal cavity from the central compartment. These data would indicate that a combination of i.p. and i.v. administration may, from the pharmacological point of view, indeed contribute to an improved treatment of minimal residual disease persisting in the peritoneal cavity.