Phase III Detoxification: Transporters of Phase 2 Products from the Cell


After the completion of Phase II conjugation, unwanted compounds are now hydrophilic and ready for excretion from the cell. However, these compounds still remain in the cell and must be transported out of the cell in order for them to be eliminated from the body. This is obviously a vital function in the detoxification process and is accomplished by none other than the efflux transporters or efflux pumps -the same efflux pumps involved in the antiporter mechanism. It is this process, of transporting Phase II conjugates out of the cell, which is now being referred to as Phase III.


Phase III transporters, for example, P-glycoprotein (P-gp), are expressed in many tissues such as the liver, intestine, kidney, and brain.  Phase III transporters are present in many tissues, including the liver, intestines, kidneys, and brain, where they can provide a barrier against xenobiotic entry, or a mechanism for actively moving xenobiotics and endobiotics in and out of cells. Since water-soluble compounds require specific transporters to move in and out of cells, phase III transporters are necessary to excrete the newly formed phase II products out of the cell.

In the liver, phase III transporters move glutathione, sulfate, and glucuronide conjugates out of cells into the bile for elimination. In the kidney and intestine, phase III transporters can remove xenobiotics from the blood for excretion from the body.  Phase III transporters act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted.

antiporter activity (p-glycoprotein or multi-drug resistance) has been defined as the Phase III detoxification system.  The antiporter is an energy-dependent efflux pump, which pumps xenobiotics out of a cell, thereby decreasing the intracellular concentration of xenobiotics.

The antiporter is an energy dependent efflux pump (transport protein), contained within the enterocytes, whose function is to export unwanted compounds immediately back into the intestines. Once the exported unwanted compound arrives back into the intestine one of several things can take place:

  • It can be eliminated in the stool
  • It can re-enter the enterocyte only to be exported back out into the intestine and start the cycle over again
  • It can re-enter the enterocyte and pass into the blood stream and travel to the liver
  • It can re-enter the enterocyte and be acted on by the Phase I CYP3A4 enzymes thereby starting the biotransformation process before it is passed into the blood stream to travel to the liver

This makes antiporter activity an important factor in the first pass metabolism of pharmaceuticals and other xenobiotics. First pass effect is the biotransformation of unwanted compounds by intestinal enzymes and the liver before the compound reaches systemic circulation.


Figure 1 Phase III Transporters:  The Antiporter

Efflux transporters / pumps serve a dual function with the Phase III terminology used to refer to both functions of:

  • Phase III metabolism – transporters act by eliminating both endogenous and exogenous Phase II conjugated metabolites from hepatocytes and other tissues
  • Antiporter action – transporters acting as nature’s gatekeeper for cellular entry by eliminating unwanted compounds pre-biotransformation

More than 350 unique human transporters have been identified. The best known and most studied transporter is the P-glycoprotein.  Efflux transporters can also be induced –increasing the transporters activity, and can be inhibited – causing substrate levels to become higher.

Table 1:  Activators and Inhibitors of Phase 3 Detoxification

Activators and Inhibitors of Phase 3








Apple Polyphenols


Sulforaphane from Cruciferous vegetables










Milk Thistle (Silymarin)

Several transport proteins (cMOAT, OAT, MRP1, MRP2, GS-X) of the phase 3 detoxification system can be enhanced by the following substances:

  • sufficient water ingestion
  • green foods
    • Spirulina
    • Chlorella
    • Barley grass
    • Wheatgrass

Prevention of absorption through trapping of potential toxins (such as surface adhesion to another molecule in the gut, like activated charcoal or kaolin clay) is an effective means of mitigating exposure; this mechanism has the requirement of some dietary adsorbent to be taken while the toxin is in transit in the GI tract. Uptake of potential toxins and their detoxification by beneficial colonic microflora could have a similar effect.

Bile Flow and Excretion

The liver’s third detoxification process involves the synthesis and secretion of bile. Each day the liver manufactures bile, which serves as a carrier in which many toxic substances are effectively eliminated from the body. Sent to the intestines, the bile and its toxic load is absorbed by fiber and excreted from the body.  However, a diet low in fiber means these toxins are not bound effectively and may be reabsorbed.

The liver’s second detoxification process involves the synthesis and secretion of bile for the elimination of modified toxins. Each day the liver manufactures approximately 1 quart of bile, which serves as a carrier in which many toxic substances are dumped into the intestines. In the intestines, the bile and its toxic load are absorbed by fiber and excreted. However, a diet low in fiber results in inadequate binding and reabsorption of the toxins. This problem is magnified when bacteria in the intestine modify these toxins to more damaging forms.

When the excretion of bile is inhibited (i.e. cholestasis), toxins stay in the liver longer. Cholestasis has several causes, including obstruction of the bile ducts and impairment of bile flow within the liver. The most common cause of obstruction of the bile ducts is the presence of gallstones. Perhaps the most common cause of cholestasis and impaired liver function is alcohol ingestion. In some especially sensitive individuals, as little as 1 ounce of alcohol can produce damage to the liver, which results in fat being deposited within the liver. All active alcoholics demonstrate fatty infiltration of the liver.

It is important to get the toxins out the the liver as fast as possible.  This can be down by increasing the flow of bile.  The role of fiber is very important in this instance since once the bile (with the toxins) is secreted into the intestines, there must be adequate fiber for the bile to bind to for elimination from the body.

Impairment of bile flow is going to reduce the bodies ability to eliminate toxins.  This is typically caused by a congested liver, inflammation and scarring of the bile duct and/or gall stones.

The compounds that help improve bile flow include:

Table 2:  Foods, Spices and Vitamins/Amino Acids that Improve Bile Flow

Improved Bile Flow












Beet root










Dandelion root












Ajowan (carom seed)


Milk Thistle (Silymarin)



Vitamins and Amino Acids





Vitamin C


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