Description: <p><b>Vitamin B12</b> = cobalamin (water-soluble vitamin; forms: methylcobalamin, adenosylcobalamin, cyanocobalamin, hydroxocobalamin). Sources: animal-derived foods; requires intrinsic factor–mediated absorption; transport via transcobalamin (TCII). Primary mechanisms (ranked):<br>
1) <b>Methionine synthase cofactor</b> → homocysteine → methionine → SAM → DNA/RNA/histone methylation (one-carbon metabolism integration).<br>
2) <b>Methylmalonyl-CoA mutase cofactor</b> → odd-chain FA / branched-chain AA metabolism; mitochondrial anaplerosis support.<br>
3) <b>Genome stability support</b> (via nucleotide synthesis + methylation balance).<br>
Bioavailability/PK relevance: Active absorption saturable (~1–2 µg/meal via IF); passive diffusion at high oral doses (~1%); serum levels tightly regulated; intracellular utilization depends on TCII uptake and lysosomal processing.<br>
In-vitro vs oral exposure: Most cancer cell studies use supraphysiologic cobalamin or manipulate one-carbon flux; effects typically reflect <b>methylation / nucleotide synthesis dependency</b> rather than direct cytotoxicity.<br>
Clinical evidence status: Essential nutrient; deficiency correction clearly beneficial; no established anticancer efficacy; epidemiology mixed (very high serum B12 sometimes correlates with cancer presence—likely reverse causality/biomarker phenomenon rather than causation).</p>
<b>Helps</b> make red blood cells, metabolize food and prevent nerve damage.<br>
<br>
<h3>Vitamin B12 (Cobalamin) — Cancer vs Normal Pathway Effects</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells (↑ / ↓ / ↔)</th>
<th>Normal Cells (↑ / ↓ / ↔)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>One-carbon metabolism (Methionine synthase → SAM)</td>
<td>↑ methylation capacity; ↑ nucleotide synthesis (proliferation support)</td>
<td>↑ genome stability; ↑ normal DNA synthesis</td>
<td>R→G</td>
<td>Methyl donor cycling</td>
<td>Supports SAM production; in rapidly dividing tumors may facilitate growth if not limiting.</td>
</tr>
<tr>
<td>2</td>
<td>DNA methylation / Epigenetics</td>
<td>↔ / ↑ (context-dependent; can restore normal methylation if deficient)</td>
<td>↑ methylation homeostasis</td>
<td>G</td>
<td>Epigenetic stability</td>
<td>Deficiency → hypomethylation/genomic instability; supplementation restores baseline rather than inducing supraphysiologic hypermethylation in most settings.</td>
</tr>
<tr>
<td>3</td>
<td>Nucleotide synthesis (via folate cycle coupling)</td>
<td>↑ proliferation support (if B12 limiting)</td>
<td>↑ normal hematopoiesis</td>
<td>R→G</td>
<td>DNA replication capacity</td>
<td>Mechanistically linked to folate; deficiency leads to megaloblastic anemia.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial metabolism (Methylmalonyl-CoA mutase)</td>
<td>↔ (supports baseline metabolism)</td>
<td>↑ mitochondrial function</td>
<td>R</td>
<td>Anaplerotic support</td>
<td>Prevents methylmalonic acid accumulation; preserves mitochondrial efficiency.</td>
</tr>
<tr>
<td>5</td>
<td>ROS</td>
<td>↔ (indirect)</td>
<td>↓ oxidative stress (deficiency correction)</td>
<td>R</td>
<td>Redox balance (secondary)</td>
<td>Effects mediated through improved mitochondrial and methylation balance.</td>
</tr>
<tr>
<td>6</td>
<td>NRF2</td>
<td>↔ (no direct axis)</td>
<td>↔</td>
<td>G</td>
<td>Adaptive response (indirect)</td>
<td>No primary NRF2-targeting activity established.</td>
</tr>
<tr>
<td>7</td>
<td>Ca<sup>2+</sup></td>
<td>↔</td>
<td>↔</td>
<td>P</td>
<td>Not a core pathway</td>
<td>No meaningful Ca²⁺ modulation axis.</td>
</tr>
<tr>
<td>8</td>
<td>HIF-1α / Warburg</td>
<td>↔ (indirect via proliferation capacity)</td>
<td>↔</td>
<td>G</td>
<td>Metabolic permissiveness</td>
<td>No direct hypoxia pathway targeting; effects are permissive rather than suppressive.</td>
</tr>
<tr>
<td>9</td>
<td>Ferroptosis</td>
<td>↔</td>
<td>↔</td>
<td>R</td>
<td>Not established</td>
<td>No defined ferroptotic mechanism.</td>
</tr>
<tr>
<td>10</td>
<td><b>Clinical Translation Constraint</b></td>
<td colspan="2">Essential nutrient; correction of deficiency critical. No validated anticancer benefit; very high serum B12 often reflects disease state rather than supplementation causality.</td>
<td>—</td>
<td>Evidence</td>
<td>Interpret epidemiologic associations cautiously (reverse causation common).</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>