Maximal load of the vitamin B12 transport system: a study on mice treated for four weeks with high-dose vitamin B12 or cobinamide.
Several studies suggest that the vitamin B12 (B12) transport system can be used for the cellular delivery of B12-conjugated drugs, also in long-term treatment Whether this strategy will affect the endogenous metabolism of B12 is not known. To study the effect of treatment with excess B12 or an inert derivative, we established a mouse model using implanted osmotic minipumps to deliver saline, cobinamide (Cbi) (4.25 nmol/h), or B12 (1.75 nmol/h) for 27 days (n = 7 in each group). B12 content and markers of B12 metabolism were analysed in plasma, urine, kidney, liver, and salivary glands. Both Cbi and B12 treatment saturated the transcobalamin protein in mouse plasma. Cbi decreased the content of B12 in tissues to 33-50% of the level in control animals but did not influence any of the markers examined. B12 treatment increased the tissue B12 level up to 350%. In addition, the transcript levels for methylenetetrahydrofolate reductase in kidneys and for transcobalamin and transcobalamin receptor in the salivary glands were reduced. Our study confirms the feasibility of delivering drugs through the B12 transport system but emphasises that B12 status should be monitored because there is a risk of decreasing the transport of endogenous B12. This risk may lead to B12 deficiency during prolonged treatment.
Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. dolild@rm.dk
Dorte L
DL
Lildballe
Elena
E
Mutti
Henrik
H
Birn
Ebba
E
Nexo
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003038:Cobamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017931:DNA Primers / Q000235:genetics; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015918:Infusion Pumps, Implantable; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000378:metabolism; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000378:metabolism; D014155:Transcobalamins / Q000378:metabolism; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine
D015415:Biomarkers; D003038:Cobamides; D017931:DNA Primers; D011956:Receptors, Cell Surface; D014155:Transcobalamins; C028176:transcobalamin receptor; C017142:cobinamide; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12