Piperine is a pungent substance found in plants of the Piperaceae family – including Piper nigrum (black pepper) and Piper longum (long pepper). These peppers have been used in Ayurvedic medicine for the treatment of various diseases and discomforts. Recent research has provided support for some of these uses and has uncovered the probable mechanism responsible for them.

Let us look at what is known about the piperine’s mechanism of action in the body.

How the body controls access to its cells

The body has several major mechanisms for controlling the exposure of its cells to nutritional and other substances. Four of these mechanisms are of interest with regard to piperine: metabolic conversion, assisted absorption, assisted exclusion, and solubilizer attachment.

Metabolic conversion involves the use of enzymes to chemically convert substances to different substances that may be less active and, in any case, are more easily carried in blood to the kidneys for excretion. The original substances are called ‘substrates’ of the enzymes; after conversion they are called ‘metabolites’. For example, an enzyme called ‘aromatase’ converts the substance testosterone into estradiol. Testosterone is a substrate of the aromatase enzyme; estradiol is a metabolite of testosterone. Although estradiol is itself an important hormone in the body, it also serves as an excretable form of testosterone. Other enzymes convert estradiol into even more easily excreted forms, such as estriol.

Assisted absorption, the second method for controlling the exposure of cells to substances, involves the use of transporter proteins in the cells of the digestive tract. These proteins actively transport substances into cells of the intestinal lining; from there they can be transferred to the blood. Assisted absorption is particularly important for ensuring that essential amino acids are available in adequate amounts.

Assisted exclusion involves the use of transporter proteins that ‘pump’ certain substances out of cells, whereupon they can be taken away by the blood. While the activities of these pumps can protect cells from toxic overloads of many substances, they can also spoil the efficacy of otherwise beneficial drugs and supplements by pumping these substances out of the cells before they can act. One of the most important such ‘pump’ proteins is p-glycoprotein, which is found in the membranes of cells in the intestines, brain, liver, pancrease, kidneys, and other tissues.

Solubilizer attachment prevents substances from entering cells by linking them chemically to a highly water-soluble substance. Not only does this alter the biological activities of the substances in question, it also makes them unable to diffuse through cell membranes. One of the important solubilizers found in the body is glucuronic acid. Substances bound to this solubilizer are usually excreted either into the urine or into the small intestine, depending upon the nature of the substance.

How piperine increases the bioavailability of many substances

Piperine has the remarkable ability to manipulate all four of these mechanisms. It inhibits a number of enzymes responsible for metabolizing drugs and nutritional substances; it stimulates the activity of amino-acid transporters in the intestinal lining; it inhibits p-glycoprotein, the ‘pump’ protein that removes substances from cells; and it decreases the intestinal production of glucuronic acid, thereby permitting more of the substances to enter the body in active form. Consequently, some of these substances are able to reach, enter, and remain within their target cells for longer periods of time than would otherwise be the case. Of course, this can be a mixed blessing – if one is using a drug for which the therapeutic level is not substantially lower than the toxic level, piperine supplementation might raise the bioavailability of the drug until its intracellular concentration exceeds the toxic threshold. On the other hand, piperine supplementation can sometimes turn a marginally effective therapeutic substance into a highly effective one simply by increasing its bioavailability and intracellular residency time. A good example of this latter phenomenon is the use of piperine to increase the bioavailability of curcumin, a supplement with broad activity against cancers, inflammation and infections. A 20 mg dose of piperine can increase curcumin’s bioavailability twentyfold.