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Biomedical subjects

I Chanarin

Publications and source records attributed to I Chanarin.

At least 37 records · Page 2Linked to original sources
PubMed1989

Cobalamin-folate interrelations.

Cobalamin deficiency leads to impaired folate function as demonstrated by markedly impaired single-carbon unit transfer into purine, thymidine and methionine. This occurs in the total absence of 'methylH4folate trapping'. In cobalamin deficiency there is impaired synthesis of formylH4folate and raised levels of endogenous formate in blood and liver. FormylH4folate and methionine reverse the effects of cobalamin deficiency. Methionine provides formate via its metabolism to methylthioribose. Recently it has been suggested that the neuropathy of cobalamin deficiency is due to impaired methylation but this was not confirmed. It is likely that defects demonstrated in marrow and liver are also the explanation for the effects of cobalamin deficiency in the CNS.

Anemia, Megaloblastic↗
PubMed1989

The recovery of circulating progenitor cells after chemotherapy in AML and ALL and its relation to the rate of bone marrow regeneration after aplasia.

Peripheral blood levels of BFU-e, CFU-GM and CFU-mix were studied serially in nine patients with acute leukaemia in remission during the period of recovery that followed induction or consolidation chemotherapy. Following 23 courses of treatment in the nine patients, the values for all three classes of progenitor were found to be higher in ALL than in AML (mean peak CFU-GM levels 5.8 x 10(3)/ml and 0.8 x 10(3)/ml respectively) and the highest levels were observed in patients recovering the most rapidly from bone marrow aplasia. Peak levels of these progenitors correlated best with the rate and extent of platelet recovery and all patients achieving blood levels of greater than 1.0 x 10(3) CFU-GM/ml had recovered greater than 100 x 10(9)/l platelets by 20 d and had peak platelet counts of greater than 400 x 10(9)/l within 40 d following chemotherapy. The peak values for circulating progenitors fell markedly after repeated courses of treatment in three of the five AML patients studied and this is likely to limit useful harvesting of such cells during later consolidation courses in this disease.

Adolescent↗
PubMed1988

In vivo oxidation of the methyl group of hepatic 5-methyltetrahydrofolate.

Methionine given parenterally to rats caused rapid disappearance of methyltetrahydrofolate from the liver and a corresponding rise in tetrahydrofolate and formyl-tetrahydrofolate concentrations. When [14C]H3--H4folate was given, methionine caused an increased [14C]0(2) excretion, indicating that oxidation of the methyl group had occurred. Methionine was more effective than S-adenosylmethionine at causing oxidation, but serine was ineffective. The lowest dose of methionine to produce an effect was 0.5 mumol, which is less than the daily dietary intake in a rat. The data suggest that the concentration of methylfolate in rat livers is controlled by the concentrations of methionine.

Adenosine↗
PubMed1988

Vegetarian diet and cobalamin deficiency: their association with tuberculosis.

To determine whether the high incidence of tuberculosis among Asiatic Indians in the United Kingdom was due to impaired killing of Mycobacterium tuberculosis by macrophages from patients deficient in cobalamin, a nutritional survey was carried out among 1187 Indians and the incidence of tuberculosis determined from medical records. The question asked was whether tuberculosis was significantly more common among life-long vegetarians compared with omnivores. The incidence of tuberculosis in vegetarians was 133 in 1000 and that in subjects on mixed diets 48 in 1000. These findings lend support to the hypothesis that dietary factors are of major importance in determining the susceptibility of Asiatic Indians to tuberculosis.

Adult↗
PubMed1987

Impaired formylation and uptake of tetrahydrofolate by rat small gut following cobalamin inactivation.

The effect of inactivation of cobalamin by N2O on the intestinal absorption of folate was studied using rat everted gut sacs. Further, in view of uncertainties about the presence of methionine synthetase in gut [1], this enzyme was measured. Everted gut sacs were incubated with [2-14C]tetrahydrofolate, and the subsequent appearance of labelled formyl- and methyl [14C] tetrahydrofolate in everted segments of small intestine of rats was studied. Considerable methionine synthetase activity was present in washed everted gut sacs but not in gut segments in the absence of such treatment. Methionine synthetase activity declined after exposure to N2O, which oxidizes and inactivates cob(I)alamin. Folate uptake by gut sacs was not affected by 24 h exposure of the animals to N2O but fell significantly after 7 days exposure. There was a significant fall in the amount of formyltetrahydrofolate formed after cobalamin inactivation and this was reversed by supplying either methionine, methylthioadenosine or sodium formate. Serine had no effect. The data support the hypothesis that methionine and methylthioadenosine act by supplying single carbon units at the formate level of oxidation.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1987

How to diagnose (and not misdiagnose) pernicious anaemia.

The diagnosis of pernicious anaemia requires the demonstration that megaloblastic haemopoiesis is present, that vitamin B12 deficiency is present and that gastric intrinsic factor is lacking. The first, generally requires marrow aspiration, the second is satisfied by a low serum B12 level and the third by B12 absorption tests with and without intrinsic factor. The reasons why these three criteria are the minimum criteria for diagnosis are discussed as well as pitfalls in the performance of tests and in interpretation of data. Finally, a low serum vitamin B12 with impaired B12 absorption improved by the addition of intrinsic factor in the absence of blood changes indicates severe atrophic gastritis but not pernicious anaemia.

Anemia, Pernicious↗
PubMed1987

Megaloblastic anaemia, cobalamin, and folate.

Developments relating to cobalamin and folate are reviewed. Current work on the relations between these two coenzymes are discussed, particularly those that have emerged in studies using nitrous oxide, which inactivates cobalamin.

Anemia, Macrocytic↗
PubMed1986

Vitamin B12 neuropathy is not due to failure to methylate myelin basic protein.

It has been proposed that the biochemical lesion in subacute combined degeneration of the cord due to vitamin B12 deficiency, is impaired methylation of residue 107 (arginine) in myelin basic protein. We have examined myelin basic protein in brains of rats in which vitamin B12 was inactivated by exposure to nitrous oxide for up to 7 days. In addition brains of fruit bats in which vitamin B12 neuropathy had been produced by feeding washed, and hence vitamin B12-free fruit, were examined. There was no difference in the methylation of arginine 107 in myelin basic protein in these animals as compared to healthy control animals. Rats given an inhibitor of transmethylation reactions (cycloleucine) showed the expected fall in methylation of myelin basic protein.

Animals↗
PubMed1985

Megaloblastic anaemia in a vegetarian Hindu community.

138 Indian patients with megaloblastic haemopoiesis were studied. All were lifelong vegetarians. The diagnosis was nutritional cobalamin deficiency in 95 and pernicious anaemia in 20; only 4 patients had folate deficiency. A third had intestinal malabsorption, 20 had features of osteomalacia, and 87 were iron deficient. Tuberculosis was diagnosed in 17. Cobalamin deficiency may have contributed to these complications via intestinal malabsorption and impaired bacterial killing of phagocytosed bacilli by cobalamin-deficient macrophages. The frequency of pernicious anaemia was the same in Indian subjects as in Caucasians.

Absorption↗
PubMed1985

Effect of cobalamin inactivation on folate-dependent transformylases involved in purine synthesis in rats.

N2O oxidizes and inactivates cob[I]alamin, and animals exposed in this way serve as models for cobalamin 'deficiency'. Such animals show a fall in activity of glycinamide ribotide transformylase and a rise in that of 5-amino-4-imidazolecarboxamide ribotide transformylase. The fall in glycinamide ribotide transformylase activity was prevented by parenteral 5'-methylthioadenosine derived from methionine. Methylthioadenosine in turn is converted into formate. Activity of glycinamide ribotide transformylase recovers after 7 days despite continued N2O inhalation, and this is probably related to restoration of methionine synthesis by induction of betaine:homocysteine transmethylase.

Acyltransferases↗
PubMed1985

Folate polyglutamate synthetase activity in the cobalamin-inactivated rat.

Exposure to N2O inactivates cob[I]alamin and interferes with the activity of methionine synthetase, of which cob[I]alamin is a coenzyme. Less directly, it stops the formation of folate polyglutamate from tetrahydrofolates. Studies on the activity of folate polyglutamate synthetase in rat liver in vivo were carried out. The synthetase activity increased after exposure to N2O for up to 48 h, but longer exposure was accompanied by a return of activity to baseline values. The rise in synthetase activity was prevented by supplying methionine, 5'-methylthioadenosine or 5-formyltetrahydrofolate. The fall in folate polyglutamate synthetase activity after 48 h was accompanied by a restoration of hepatic synthesis of folate polyglutamate despite continuation of N2O exposure.

Amide Synthases↗
PubMed1985

Role of folate dependent transformylases in synthesis of purine in bone marrow of man and in bone marrow and liver of rats.

The activity of the two folate dependent enzymes supplying carbon 2 and carbon 8 of the purine nucleus was assayed in the bone marrow of rats and man, as well as in rat livers. The activity of both enzymes was several fold greater in marrow than in liver. Inactivation of cobalamin by exposure to nitrous oxide did not affect the enzymes in rat marrow cells, although an appreciable effect on hepatic enzymes was found. The depression of hepatic glycinamide ribotide (GAR) transformylase in rats exposed to nitrous oxide was prevented by supplying a formate precursor, methylthioadenosine. There was a considerable rise in the activity of GAR transformylase in human marrow cells from patients with megaloblastic anaemia due to cobalamin deficiency but no change in activity in marrow from patients deficient in folate.

Acyltransferases↗