Subtitle: Why Petri dish studies don’t always translate into benefit for patients
While I am an enthusiastic supporter of naturally-derived compounds as the source of drugs, I am extremely disappointed and dismayed at how non-prescription natural products are promoted indirectly for disease treatment. Patients with cancer or HIV/AIDS are those most often preyed upon by manufacturers of the “next great cure” – hence, the convergence of cancer and natural products leads me to today’s post, the first in a multi-part series of general comments on the marketing of herbal or dietary supplements.
Case in point for this series is the spice, turmeric, and the pure compound derived from it, curcumin. I could pick any natural compound, including some on which I work in my own laboratory, but curcumin is special because of the amount of press and scientific attention it has received. The literature abounds with over 1700 reports, mostly from studies of cancer cells grown in Petri dishes, on how curcumin can kill cancer cells, act as an antinflammatory agent, among other activities.
There is no doubt that the results in these reports are true for cells growing in a dish, but extrapolating those results to a whole person taking a curcumin supplement is a very long stretch that requires far more evidence. Most importantly, and the subject of this and the next post is the following question:
Do concentrations of curcumin (or any compound) with anticancer effects in cell culture actually occur in the bloodstream of patients who take dietary supplements containing the compound?
To understand the translation of cell culture studies to the whole person, we must first consider all of the systems operating in the human body that are not present when human cells are grown in plastic Petri dishes.
In my first week of pharmacology lectures to pharmacy and medical students, or in my two-hour “Mini-Med School” lecture to the general public, we talk about the barriers to drug action in discussing the concepts of drug absorption, distribution, metabolism, and excretion, often called ADME to refer collectively to these four important physiological factors that influence drug action.
These concepts apply to any chemical taken into the body (we sometimes use the “xenobiotic” to refer broadly to anything we take in). These concepts apply regardless of whether the substance ingested is a chemical found naturally in plants and herbs or a chemical that is synthesized at the lab bench by a chemical or pharmaceutical company.
When we ingest a drug orally, there are many determinants to how much of that drug gets into the bloodstream and, ultimately, to the site of its desired action. None of these processes are in operation in Petri dish studies, except in highly specialized experiments.
So let’s consider what additional hurdles a drug, herbal ingredient, or vitamin must overcome to be of any use to the human body.
The first barrier to drugs taken by mouth is the highly acidic environment of the stomach. Next, are the epithelial cells lining the stomach and, more importantly, the twenty-some-odd feet of the small intestine. Some drugs are poorly absorbed from the intestine into the bloodstream and some portion, or all of it, simply passes through the intestines unabsorbed and out with the feces. For drugs that have characteristics that allow them to be absorbed, blood from the intestines then must pass through the liver (via the hepatic portal vein) before being distributed to the rest of the body.
The liver is a glorious organ. The liver has a tremendous capacity for metabolizing drugs and chemicals to inactive substances, as one might expect for an organ that has evolved over millions of years being exposed to chemicals (and toxins) normally encountered in our omnivorous diet. I often refer to the liver as “the catalytic converter of the body.” In fact, many drugs and toxic substances are so effectively inactivated by liver metabolism that we call this inactivation the “first-pass effect” – to indicate the percentage of drug metabolized during its first past through the liver after being absorbed in the intestine. The enzymes of the liver even have the capacity to metabolize chemicals that have not yet even been invented! (I should also note to the more technical audience that the intestinal epithelium itself contains some of the same drug metabolizing enzymes found in the liver, such that metabolism can start even earlier).
For a drug to have its desired effect, it must also be distributed to its site of action, rapidly and in high enough concentrations to have an effect. All this occurs while our blood is being very rapidly filtered by our kidneys. Our kidneys are amazing filtration systems, clearing our blood of water-soluble metabolites with a capacity of 180 to 400 liters per day – compared with the 4 or so liters of liquid in our 5.5 liters of blood, that means that the kidneys filter our blood completely almost 100 times a day.
Some drugs that do make it into the blood in high concentrations may not get to certain sites, or compartments. For example, the brain is well-protected from many types of drugs by cell junctions in brain blood vessels that create what is known as “the blood-brain barrier.” Drugs that work best in the brain are usually more fat-soluble than most: drugs like anesthetics, opioid pain killers, antidepressants, and drugs for Parkinson’s disease – since they can bypass these cellular junctions and get across the cells. Here’s a fun fact: the non-sedating antihistamines like Claritin don’t cross the blood-brain-barrier as well as sedating antihistamines like Benadryl. If you could somehow put Claritin directly into the brain, it would be just as sedating as Benadryl.
Once drugs are in the bloodstream, they are cleared from the blood at a certain rate, some quickly, some slowly, depending on the collective contribution of all the processes we have described. Some drugs get tagged, or conjugated, with a sugar-molecule, and that permits the kidney to actively secrete it into the urine, leading to its elimination. But when those sugar-conjugated drugs (called “glucuronide conjugates”) find their way back into the intestine (via secretion in the bile), enzymes in the intestine can clip off the sugar molecule, releasing free and active drug that has a chance to get reabsorbed and do its thing again. Some drugs are broken down by enzymes in the blood. On the other hand, a little known fact is that some drugs may even be made more active by virtue of chemical metabolism, a process observed with the pain-killer and cough suppressant, codeine, whose action is due mostly to its conversion to the active metabolite, morphine.
All of these competing effects go into the decision of how much of a drug dose is given and how often that dose must be taken each day.
So, without trying to be too confusing, the message here is that there is a lot more to consider when reading a report on “scientific research” about an herb or supplement, and then deciding whether it is useful for treating cancer.
In the next installment of this series, we will look closely at specific studies of curcumin and the studies published by a well-known curcumin manufacturer to help make some sense out of claims made for the anticancer activity of this natural product.