When Drugs Meet Nutraceuticals:Cytochrome P450 Interactions

With the current estimates of one in every two men and one in every three women being diagnosed with cancer in their lifetime, chances are every naturopathic doctor will see patients with this disease. Many of these patients will be receiving conventional treatments, including chemotherapy. While molecularly targeted therapies will make non-specific cytotoxic chemotherapies obsolete someday, that time has not yet arrived.

When a patient decides to undergo chemotherapy, one of our roles is to maximize the effectiveness of the treatment. This means that we must avoid any adverse interactions of natural medicines with the chemotherapeutic agents, including changing the metabolism of the drugs. Metabolism of many commonly used drugs involves cytochrome P450 (CYP) enzymes, a pathway that can be influenced by other drugs, herbs, lifestyle factors and foods.

There are currently 57 families of CYPs characterized in humans, and hundreds more characterized in fungi, plants, bacteria and animals. Nomenclature for these enzymes is based on the similarity of the amino acid sequences, designated by a number, letter, or combination (i.e., CYP3A4). The role of CYPs in humans can be divided into two categories: 1) biotransformation, which involves metabolism of a wide variety of endogenous and exogenous substrates, and 2) steroid biosynthesis, which encompasses the formation of bile acids, steroidal substances and lipid derivatives such as thromboxane A2.

Biotransformation is commonly known as phase I detoxification in naturopathic medicine. Phase I enzymes belong to CYP1, CYP2 and CYP3 families and metabolize over 90% of currently used drugs, with CYP3A4 alone accounting for over 50% of drugs metabolized. These CYP enzymes are also involved in the bioactivation or degradation of many chemotherapeutic agents (see table 1). Interestingly, it is thought that some CYP enzyme systems have evolved as a means for animals and mammals to metabolize the toxins found in plants. This may be the reason that many of the chemotherapeutic agents that are metabolized through the CYP system are plant derivatives (i.e., paclitaxel, vincristine, irinotecan).

While there is little evidence available on the concomitant use of chemotherapeutic agents and natural agents that inhibit or induce CYP enzymes, evidence with other drugs suggests that interactions are likely to affect drug efficacy. One of the most widely publicized interactions is that of grapefruit juice with blood pressure medications, a result of inhibition of CYP3A4. Inhibition of this enzyme slows metabolism of the drug leading to higher than expected serum concentrations and possible hypotension. Another example is St. John’s Wort, which has been well proven to induce CYP3A4 leading to rapid clearance of drugs metabolized through this enzyme. This interaction has gained a lot of attention in recent years due to case reports of organ transplant patients rejecting implanted tissue when immunosuppressive drugs were cleared too quickly.

Other natural agents that have been proven to affect CYPs are Allium sativum, Piper methysticum, Silybum marianum, Glycyrrhiza glabra, Angelica sinensis, resveratrol, curcumin, capsaicin, quercetin and isothiocyanates from broccoli. Given the complex phytochemistry of botanicals, there is a high likelihood that many herbs will interact with CYPs; indeed, this may be the mechanism through which they exert a therapeutic action.

The cautionary note regarding interactions is not meant to discourage the use of natural agents. Interactions with CYPs are inevitable given the broad spectrum of substrates these enzymes bind and the highly responsive nature of the enzyme to its cellular environment. It is essential to understand, however, that when the therapeutic window of a drug is narrow, changes in drug metabolism can push the concentration of the drug below or above the therapeutic range. Pushing any drug outside of its therapeutic window will lessen the efficacy of the drug, and may increase the toxicity to the patient. Some drugs with narrow therapeutic ranges include immunosuppressive medications, central nervous system anesthetics and chemotherapeutic agents.

While not all chemotherapeutic agents interact with CYPs, it is essential for us to be aware of possible interactions and take precautions to avoid interfering with the efficacy of the conventional treatments. Prudence on selection and timing of herbs and other natural agents when a patient is receiving chemotherapy is in the best interest of the patient. This requires us to recognize the irony of practicing “First, Do No Harm” in an integrative oncology setting.

Author: NDNR