Transport of therapeutic cyanocobalamin in the congenital deficiency of transcobalamin II (TC II)

Hall, Charles A.; Hitzig, W. H.; Green, Pamela D.; Begley, James A.

doi:10.1182/blood.v53.2.251.251

Cited by 39 publications

(5 citation statements)

References 26 publications

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“…The HepG2 hepatocytes, derived from a human hepatoma, were found to have receptors for TC II-Cbl, internalized the complex, released the Cbl from the TC 11, converted it to coenzyme forms of Cbl, and released Cbl into the environment. The conditions and dynamics of the binding of TC II-Cbl by HepG2 cells were similar to those of other human cells.Those studied in the greatest detail include HeLa cells (Finkler and Hall, 1967;Haus et al, 1979;Hall and Green , 1978;Hall et al, 1979), fibroblasts (Youngdahl-Turner et al, 1978), an established line of lymphoblasts (Hall and Green, 1978), and stimulated peripheral lymphocytes (Hall 1984). The binding to HepG2 cells was saturable, Ca2' dependent, and inhibited by a large excess of TC II-Cbl (Fig.…”

Section: Discussionmentioning

confidence: 99%

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The metabolism of cobalamin bound to transcobalamin II and to glycoproteins that bind Cbl in HepG2 cells (human hepatoma)

Hall

Green-Colligan

Begley

1985

Journal Cellular Physiology

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The binding, internalization, processing and release of labeled cyanocobalamin (CN[57Co]Cbl) bound to human transcobalamin II (TC II) were studied in HepG2 cells, a line of hepatocytes derived from a human hepatoma. The cells bound the TC II-Cbl by specific, high affinity receptors. Within the cell, the CN-Cbl was promptly freed from TC II and the CN-Cbl converted to more active forms including adenosyl Cbl (AdoCbl) and methyl Cbl (MeCbl). Whereas free labeled Cbl was still present at 72 hours after entry, the cells also bound Cbl to an intracellular binder (ICB) presumed to represent the holo enzymes dependent on Cbl. At levels of TC II that saturated the receptors for TC II-Cbl, much of the Cbl entering the cells remained free and was converted to AdoCbl. Under these circumstances the cells released free Cbl, mostly AdoCbl. Human R type binders of Cbl, which are glycoproteins and some having a terminal galactose, were bound by the HepG2 cells. The binding was characteristic of the receptor system responsive to a terminal galactose, or asialoglycoproteins, but was inconsistent and of low affinity. Cbl bound to R binder was internalized and converted to coenzyme forms of Cbl, but the process was much less effective than when the Cbl entered via the TC II receptor system. It was concluded that the receptors for R-Cbl were unlikely to contribute to the physiologic transport of Cbl in man, but may function in some yet unknown way.

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Section: Discussionmentioning

confidence: 99%

“…21, and the receptor can be considered specific. The principal function of TC I1 appears to be in providing a much more efficient uptake of Cbl by hepatic and other human cells (Finkler and Hall, 1967;Hall and Green, 1978;Hall et al, 1979;Hall, 1984) than would prevail if the Cbl were free or bound to R binder.…”

Section: Discussionmentioning

confidence: 99%

The metabolism of cobalamin bound to transcobalamin II and to glycoproteins that bind Cbl in HepG2 cells (human hepatoma)

Hall

Green-Colligan

Begley

1985

Journal Cellular Physiology

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“…[45][46][47][48] HeLa cells internalized only 1-2% of free B12 with respect to holo-TC. 45 It was later concluded that free B12 supported cell growth ca. 100 to 1000-fold less efficiently than holo-TC.…”

Section: Affinity Of B12 Derivatives Towards Transport Proteinsmentioning

confidence: 96%

“…This uptake was, nevertheless, less efficient. [45][46][47][48] HeLa cells internalized only 1-2% of free B12 with respect to holo-TC. 45 It was later concluded that free B12 supported cell growth ca.…”

Section: Affinity Of B12 Derivatives Towards Transport Proteinsmentioning

confidence: 96%

Cellular uptake of metallated cobalamins

et al. 2016

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Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the β-axial ligands (CN(-) and H2O, respectively), were included as control samples. The results indicated that B12 derivatives delivered cisplatin to both cellular cytosol and nuclei with an efficiency of one third compared to the uptake of free cisplatin cis-[Pt(II)Cl2(NH3)2]. In addition, uptake of charged B12 derivatives including [Cbl-OH2](+), [{Co}-CN-{cis-PtCl(NH3)2}](+), [{Re}-{Co}-CN-{cis-PtCl(NH3)2}](+), and [{Co}-CN-{trans-Pt(Cyt)(NH3)2}](2+) (Cyt = cytarabin) was high compared to neutral B12, which implied the existence of an additional internalization pathway for charged B12 vitamin analogs. The affinities of the charged B12 derivatives to the B12 transporters HC, IF and TC were similar to that of native vitamin B12.

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“…Less is known about the uptake of Cbl in the absence of TC II, although Berliner and Rosenberg demonstrated that platelets were able to take up appreciable amounts of vitamin B 12 in the absence of transcobalamin via a separate process [22]. Hall et al (1979) also showed that HeLa cells were able to take up free vitamin B 12 in the absence of transcobalamin and that this led to the synthesis of both methyl- and 5′-deoxyadenosyl-cobalamin, suggesting that the vitamin B 12 had entered both the cytoplasm and the mitochondria [23]. More recently, studies carried out in thymocytes [24] and synaptosomes [25] provide evidence that cyanocobalamin, which has a similar structure to hydroxycobalamin, is able to cross the plasmalemma in the absence of TC II when applied in vitro at supraphysiological concentrations.…”

Section: Introductionmentioning

confidence: 99%

Hydroxycobalamin Reveals the Involvement of Hydrogen Sulfide in the Hypoxic Responses of Rat Carotid Body Chemoreceptor Cells

et al. 2019

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Carotid body (CB) chemoreceptor cells sense arterial blood PO2, generating a neurosecretory response proportional to the intensity of hypoxia. Hydrogen sulfide (H2S) is a physiological gaseous messenger that is proposed to act as an oxygen sensor in CBs, although this concept remains controversial. In the present study we have used the H2S scavenger and vitamin B12 analog hydroxycobalamin (Cbl) as a new tool to investigate the involvement of endogenous H2S in CB oxygen sensing. We observed that the slow-release sulfide donor GYY4137 elicited catecholamine release from isolated whole carotid bodies, and that Cbl prevented this response. Cbl also abolished the rise in [Ca2+]i evoked by 50 µM NaHS in enzymatically dispersed CB glomus cells. Moreover, Cbl markedly inhibited the catecholamine release and [Ca2+]i rise caused by hypoxia in isolated CBs and dispersed glomus cells, respectively, whereas it did not alter these responses when they were evoked by high [K+]e. The L-type Ca2+ channel blocker nifedipine slightly inhibited the rise in CB chemoreceptor cells [Ca2+]i elicited by sulfide, whilst causing a somewhat larger attenuation of the hypoxia-induced Ca2+ signal. We conclude that Cbl is a useful and specific tool for studying the function of H2S in cells. Based on its effects on the CB chemoreceptor cells we propose that endogenous H2S is an amplifier of the hypoxic transduction cascade which acts mainly by stimulating non-L-type Ca2+ channels.

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Transport of therapeutic cyanocobalamin in the congenital deficiency of transcobalamin II (TC II)

Cited by 39 publications

References 26 publications

The metabolism of cobalamin bound to transcobalamin II and to glycoproteins that bind Cbl in HepG2 cells (human hepatoma)

The metabolism of cobalamin bound to transcobalamin II and to glycoproteins that bind Cbl in HepG2 cells (human hepatoma)

Cellular uptake of metallated cobalamins

Hydroxycobalamin Reveals the Involvement of Hydrogen Sulfide in the Hypoxic Responses of Rat Carotid Body Chemoreceptor Cells

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