Orange Juice Increases Nutrient Absorption By Inhibiting P-glucoprotein

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It is known that Piperine extract found in black peppers can act as a supplement absorption booster. Orange juice can do the same thing with it's "methoxyflavones" via inhibiting the so called P-glycoprotein found in the gut and liver and so can make other substances more bioavailable.

Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. - PubMed - NCBI

Full PDF available here


The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated.
The uptake of [(3)H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [(3)H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 microM), an inhibitor of P-gp.
No significant effect on the uptake of 3-O-[(3)H]methylglucose or [(14)C]phenylalanine by Caco-2 cells was found, compared with the control.
When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [(3)H]vinblastine uptake.
Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8-heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin).
HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [(3)H]vinblastine by Caco-2 cells in a concentration-dependent manner.
The order of potency of these compounds at the concentration of 50 microM was tangeretin > HMF > nobiletin.

None of these methoxyflavones inhibited 6beta-hydroxylation of testosterone catalyzed by CYP3A4.
The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [(3)H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA).
We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp.
They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.
 

Light

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That should mean that Orange Juice increases the bioavailability of Emodin too.

Piperine increases the absorption of Emodin by more than 200% by inhibiting its glucuronidation:
Beneficial Pharmacokinetic Drug Interactions: A Tool to Improve the Bioavailability of Poorly Permeable Drugs

But it seems the Piperine:Emodin ratio is 1:1
Effect of piperine on the bioavailability and pharmacokinetics of emodin in rats. - PubMed - NCBI

And Piperine increases the biosynthesis and/or inhibits the degradation of serotonin:
Black Pepper Piper Nigrum Increases Serotonin Synthesis

plus black pepper might be pretty toxic.

Can anyone estimate how much Orange Juice it would take to, say, Double the absorption of emodine?
 

Sativa

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Why not just buy 95% piperine powder online?
I purchased 50g via a common bidding site, for use in my botanical tinctures.

Alternatively, extracting your own can be a fun experience. It forms wonderful yellow crystals, and the process is verging on easy/straight-forward.
 

Light

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Why not just buy 95% piperine powder online?
I purchased 50g via a common bidding site, for use in my botanical tinctures.

Alternatively, extracting your own can be a fun experience. It forms wonderful yellow crystals, and the process is verging on easy/straight-forward.
Piperine increases serotonin,
I'm trying to find a way to enhance absorption of Emodin without causing potential damage somewhere else.
 

Sativa

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Piperine increases serotonin
This could be one reason why:
MAO Inhibition
Piperine inhibits rat MAO-A in a dose-dependent manner with an IC50 value of 49.3 microM. It inhibits MAO-B in a dose-dependent manner with an IC50 of 91.3 microM.[8]
source: Piperine - HerbPedia

Personally, i don't feel the serotonin synthesis from piperine is significant enough to be worried about. Speaking from a 'pharmacological' perspective here. But, if you are already in a state of excess serotonin, or a related state, then perhaps piperine or other pro-serotonin substances (MAO inhibitors etc) might be undesirable.

Here's some insight into the mechanism that influences serotonin transport, directly influencing serotonin levels. This knowledge can be used to encourage reduced serotonin levels etc
However, some online research can reveal what this receptor does.
5-HT2A, which is on the outside of the cell membrane, is attached to a protein inside the membrane that activates the enzyme phospholipase C. Phospholipase C splits apart the molecule phosphatidylinositol 4,5-bisphosphate inside the membrane. This becomes two molecules: inositol triphosphate, and diacylglycerol. Both of these have the same effect:

Their function is to increase the amount of calcium in the cell and to increase the amount of the enzyme Protein Kinase C.
The function of increasing calcium in the cell also to release more PKC. PKC is an enzyme that binds to cell receptors and attaches a phosphate group to them, which inactivates them and pulls them inside the cell. Dopamine receptor downregulation is done this way, and the process is similar in serotonin cells.
When PKC is activated, many receptors get downregulated. I'm trying to figure out exactly which ones are downregulated, but I know of two that are. The serotonin transporter, the protein that brings serotonin back into the cell after it has been used in the synapse, is phosphorylated by PKC, which deactivates the transporter and pulls it inside the cell. One of PKC's functions is as a Serotonin Reuptake Inhibitor, but it does this by phosphorylating the cell receptor instead of blocking it. This increases the amount of serotonin in the synapse and the length of time the serotonin stays in the synapse. I think this will make the serotonin cell fire much more often, but I'm not 100% sure what effect this will have. The article says this will decrease the currents caused by this, but I'm not exactly sure what this means.
http://neuro.cjb.net/content/17/1/45.full

Another function of PKC is to inhibit the GABA-A receptors on cells in the prefrontal cortex. This would allow for higher functioning of the frontbrain. GABA-A is an inhibitory receptor, meaning if it is activated it would slow down the functioning of the cells it is attached to. If GABA-A receptors in the part of the brain controlling the highest levels of thought were deactivated it would allow for higher thinking.
http://neuro.cjb.net/content/21/17/6502.full
 
Last edited:

Sativa

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Actually, via piperine's 5-HT1A receptor activation, this directly reduces/dampens the activity of all other serotonin 'receptors'...
 
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