Improving Bioavailability of Various Phytochemicals (great article)

Designing a Cancer Fighting Diet
June 16, 2011 By alex

Over the last few years, cancer fighting diets have received a lot of attention due to the findings that certain plant phytochemicals (also known as: Nutraceuticals), can provide an additional means of regulating the genes and processes that drive the initiation and progression of cancer. In this article, we will show you how you can utilize combinations of nutraceuticals to greatly improve their performance.

Unfortunately, in order for nutraceuticals to inhibit cancer cells, they must be able to reach certain blood (plasma) concentrations, typically in the uM (micromolar) range. However, due to metabolic processes, the plasma concentration never naturally reaches higher than the nM (nanomolar) range. The amount and length of time a neutraceutical remains in the body is referred to as its bioavailability. The limited bioavailability of most nutraceuticals has been a significant roadblock to their clinical application.

However, there are approaches that can be used to increase the bioavailability of a nutraceutical and lower the plasma concentrations required for cancer fighting properties. In this article, we will show you how you can utilize combinations of nutraceuticals to greatly improve their performance. We will use the example of resveratrol, which is found in the skin of red grapes and other fruits, as it’s a commonly used nutraceutical that has been shown to have a proven role in inhibiting many cancers.

Although 70% of the resveratrol dose taken orally is absorbed by the body, the bioavailability of resveratrol is low because it is rapidly metabolized in the intestines and liver into conjugated forms (glucuronate and sulfonate). For example, with a 25 mg oral dose, only trace amounts (below 5 ng/mL) of free resveratrol can be detected in the blood. This is far below the amount required for its anti-cancer benefits to be realized. Furthermore, oral administration of doses higher than 3000 mg per kg of body weight can be dangerous.

Clearly, the low bioavailability of resveratrol limits its therapeutic use. However, it is possible to greatly improve resveratrol bioavailability by simultaneously incorporating other nutraceuticals that inhibit its metabolic break down.

There is a synergistic effect typically found when combining certain nutraceuticals that is most likely explained by an over-saturation of the metabolic enzymes and pathways that degrade these nutraceuticals individually. We can use this knowledge to improve the bioavailability of resveratrol in two ways:

* Through the use of combinations of nutraceuticals that specifically target the metabolic enzymes; and

* By over-saturating the metabolic enzymes, using phytochemicals that compete to bind to them.

The Metabolic Processes That Limit Resveratrol Bioavailability:

There are three processes that inhibit the bioavailability of most nutraceuticals and drugs. This occurs when they attempt to cross the barrier from the intestines into the blood vessels that go to the liver. Here they are removed by ABC transporters and phase 1/II enzymes, referred to as metabolic enzymes. If they do reach the liver, they are attacked by a higher concentration of these enzymes, in addition to monoamine oxidase enzymes (MAOs).

ABC Transporters:
These transporters pump nutraceuticals (and drugs) out of the barrier that exists between the intestines and the blood vessels (enterocytes), back into the intestines. Cancer cells increase the amount of ABC transporters such as breast cancer resistant protein (BCRP) and muti-drug resistance protein 2 (MDRP2).

Phase 1 Enzymes:
These enzymes target nutraceuticals and drugs with biochemical tags that allow them to be excreted. One phase 1 enzyme, CYP3A4, is responsible for metabolizing the majority of nutraceuticals and drugs.

Phase II Enzymes:
Phase II enzymes work by adding a sulfo-moiety (SULTs) or a B-glucuronide group (UGTs) to the target nutraceutical or drug. The tagged nutraceutical is then recognized by the ABC transporters and excreted back into the intestines.

MAO Enzymes:
These gut enzymes break down and inactivate nutraceuticals by removing functional components.

The following section outlines the metabolic processes involved in the breakdown of resveratrol and includes a selection of nutraceuticals that inhibit these processes. When the following nutraceuticals are combined in specific amounts, they greatly improve the bioavailability of resveratrol by inhibiting its breakdown and excretion.

ABC Transporters:
MRP2 – Inhibited by EGCG (green tea), Quercetin (Red onion), Apigenin (Parsley)

BCRP – Inhibited by Apigenin, Hesperetin (Peppermint), Naringenin (Rosemary)

Phase 1 Enzymes:
CYP3A4 – Inhibited by Naringenin, Kaempferol (Basil, Fennel), Grapefruit juice

Phase II Enzymes:
SULTs – Inhibited by Kaempferol, Apigenin, Genistein, Curcumin

UGTs – Inhibited by EGCG/Quercetin/BiochaninA, Curcumin (Tumeric), Piperine (Pepper)

MAO Enzymes:
MAOA – Inhibited by Quercetin, Harmine, Harmaline (grapes, avocados, blackcurrants)

Conclusion:

Including all types of nutraceuticals based on their characterized mechanism can maximize the synergistic effect and therefore lead to more of the cancer fighting properties of these substances getting through to your cells and therefore, directly influencing your cancer. Please contact us if you are interested in learning more about CTOAM’s personalized gene-targeted nutraceutical diets.