Dihydrofolate reductase is present in brain

Pollock, Robert; Kaufman, Seymour

doi:10.1111/j.1471-4159.1978.tb07059.x

Cited by 32 publications

(11 citation statements)

References 14 publications

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“…DHFR is present in different regions of rat brain (3), and studies on the conversion of 7, to BH4 in brain preparations reinforced the proposal that DHFR mediates the final step in the de novo synthesis of BH4 (4,5). Lipophilic DHFR inhibitors, which differ from methotrexate (MTX) by their rapid, temperature-insensitive entry into cells (6,7) and which have potential for the treatment of brain tumors, might inhibit the synthesis of BH4, thereby impairing the formation of dopamine and serotonin.…”

mentioning

confidence: 92%

Biosynthesis of tetrahydrobiopterin by de novo and salvage pathways in adrenal medulla extracts, mammalian cell cultures, and rat brain in vivo.

Nichol¹,

Lee²,

Edelstein³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

106

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Communicated by George H. Hitchings, December 13, 1982 ABSTRACT Mammalian cells and tissues were found to have two pathways for the biosynthesis of tetrahydrobiopterin (BH4): (i) the conversion of GTP to BH4 by a methotrexate-insensitive de novo pathway, and (ii) the conversion of sepiapterin to BH4 by a pterin salvage pathway dependent on dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) activity. In a Chinese hamster ovary cell mutant lacking dihydrofolate reductase (DUKX-BII), endogenous formation of BH4 proceeds normally but, unlike the parent cells, these cells or extracts ofthem do not convert sepiapterin or 7,8-dihydrobiopterin to BH4. KB cells, which do not contain detectable levels of GTP cyclohydrolase or BH4 but do contain dihydrofolate reductase, readily convert sepiapterin to BH4 and this conversion is completely prevented by methotrexate. In supernatant fractions of bovine adrenal medulla, the conversion of sepiapterin to BH4 is completely inhibited by methotrexate. Similarly, this conversion in rat brain in vivo is methotrexate-sensitive. Sepiapterin and 7,8-dihydrobiopterin apparently do not enter the de novo pathway of BH4 biosynthesis and may be derived from labile intermediates which have not yet been characterized.

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mentioning

confidence: 92%

Biosynthesis of tetrahydrobiopterin by de novo and salvage pathways in adrenal medulla extracts, mammalian cell cultures, and rat brain in vivo.

Nichol¹,

Lee²,

Edelstein³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Low serum Mate levels have also been found in other DHPR-deficient patients (Kaufman et al, 1975), probably because DHPR may play a role in keeping Mate in the tetrahydro form (Pollock and Kaufman, 1978). Even if both our patients were given Mate supplementation (folic acid 15 mg day-t) patient 1 had a very low plasma level of tetrahydrofolic acid (0.5 ngml-a; normal values greater than 2.6ngml-1).…”

Section: Discussionmentioning

confidence: 71%

Cranial computerized tomography in dihydropteridine reductase deficiency

Longhi

Valsasina

Buttè

et al. 1985

J of Inher Metab Disea

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Dihydropteridine reductase deficiency is a rare cause of hyperphenylalaninaemia, characterized by severe and progressive neurological impairment, despite early and accurate dietary control of plasma phenylalanine. We describe two girls, diagnosed at 17 and 14 months of age, respectively, and immediately treated with L-dopa, 5-hydroxytryptophan and carbidopa. In spite of an adequate dietary and pharmacological treatment, the clinical and neurological pictures progressively worsened. Repeated cranial computerized axial tomography scans showed degeneration of the white matter and, in one case, calcification of the basal ganglia. The possible association of this last finding with folate depletion is discussed.

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“…CNS involvement in non-I Hodgkin's lymphoma and acute lymphocytic leukaemia may be prevented or treated by repeated medium or high dose MTX combined with FA rescue (Freeman et al, 1983;Balis et al, 1985). Data were missing on the possibility of an adverse accumulation of FA in CSF in such protocols; in addition, as dihydrofolate reductase is present in the brain (Pollock & Kaufman, 1978), information is required on the appropriate systemic FA dose for neutralisation of excessive MTX exposure in CSF (Cohen et al, 1986). The findings of the present study may help to clarify these points.…”

Section: Resultsmentioning

confidence: 99%