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Poison in the medicine

Harmful effects limit the potential therapeutic uses of curcumin

WWW.SXC.HUTurmeric: The extract of Indian saffron, used as a spice, is rich in curcuminWWW.SXC.HU

Curcumin, a substance found in the orange-yellow powder extracted from turmeric, also known as Indian saffron (Curcuma longa), can apparently help to fight several types of cancer, Parkinson’s disease and Alzheimer’s disease, and even to delay aging. Used for four thousand years in certain oriental cultures, only in the last few years has it become an object of investigation of western science, with surprising results in some cases and alarming in others. Studies conducted at the University of São Paulo in Ribeirão Preto (USP-RP), inner-state São Paulo, indicate that in low dosages curcumin prevents damage from toxic compounds to the genetic material of cells. In high dosages, however, curcumin may even kill cells.

The media, avid for health tips, has recently started treating curcumin as a panacea. A routine coloring agent in the food industry, it can be found in a wide range of products, from biscuits to ice-cream, from soups to margarine. It also forms the basis of condiments such as curry. Indeed, in India, in keeping with the country’s typical diet, people consume as much as two grams of curcumin a day. In western countries, where the amount of curcumin in food is far lower, the hope that curcumin may improve the quality of life and prevent illnesses has transformed it into a food supplement.

However, some researchers warn us: it is well worth taking into account an old saying according to which the difference between a medicine and a poison is the dose – an adaptation of what was supposedly written in the sixteenth century by Paracelsus, the Swiss physician, botanist and alchemist. This is basically what is suggested by the research studies of the group headed by Lusânia Maria Greggi Antunes, a researcher at the School of Pharmaceutical Sciences of USP in Ribeirão Preto. “It was highly publicized at the end of last year, even on TV shows, that curcumin supposedly could protect against cancer, but all that was said was the greater the consumption, the greater the protection”, states Lusânia. “But we know, based on the data available, that this isn’t quite the case”. Researchers from the University of Seville have also warned about the risk-benefit relation of curcumin as a therapeutic agent.

The group from Ribeirão Preto was originally interested in studying the antimutagenic potential of curcumin, i.e., its capacity to diminish damages and changes in the genetic material (DNA) of the cells. “We began our studies by trying to observe the reduction of damage in the structure of the chromosomes and then in the sequence of the DNA itself”, says the researcher. The tests were carried out with cells (in vitro) and with animals (in vivo), to find out whether curcumin, whose antioxidant action has already been demonstrated, might also avoid mutations in cells’ genetic material.

These research studies started more than 10 years ago and today form a body of technical literature that justifies the warning. In its earliest tests, Lusânia’s group used an ovary cell culture from a Chinese hamster, chosen for its large chromosomes. After treating the cells with the chemotherapy drug bleomycin, known to be mutagenic and used to treat leukemia, and with radiation, also capable of damaging genetic material, the researchers applied different concentrations of curcumin to three different cell groups. Curcumin was expected to reduce chromosome changes. However, a surprise was in store for the researchers. The lower dosages (2.5 and 5 micrograms of curcumin per milliliter) did have an antimutagenic effects, whereas the higher dosage, 10 micrograms per milliliter, had the opposite effect, causing more mutations than those observed in cells that had not been treated with curcumin. Given these results, the conclusion was that curcumin does not always produce beneficial results. Too large a quantity can have the opposite effect of lower concentrations and the drug becomes a poison.

LUCIEN MONFILS/WIKIMEDIA COMMONSIn flowers: Indian saffron, a native plant of southern AsiaLUCIEN MONFILS/WIKIMEDIA COMMONS

Recently, some studies have begun suggesting that curcumin, besides  antioxidant properties (it reduces the formation of the free radicals that damage cells) may also have a neuroprotective effect, which could transform it into a potential candidate for fighting currently incurable neurological diseases, such as Parkinson’s or Alzheimer’s. The pharmacist Leonardo Mendonça, from Lusânia’s group, also tested this assertion in 2009, in an in vitro study conducted with rat cells called PC12, which came from the adrenal gland and were precursors of neurons.

To induce cell damage, the researchers employed cisplatin, an aggressive chemotherapy drug, in different concentrations. As in the studies using ovary cells, they used varied doses of curcumin to assess its possible protective effect. The results were essentially the same: at lower concentrations, curcumin helped to protect the cells from the deleterious effects of chemotherapy. However, in higher doses, the effect was inverted and damage was even greater than that observed in the cells treated only with cisplatin and no curcumin.

At this point, it had become clear that the effect of curcumin was not always protective. But why? Apparently, after a given dose, the substance started to contribute to the formation of free radicals, rather than inhibiting it. The precise molecular mechanism behind this, however, is still far from clear. The most intriguing thing is that the experiments of Lusânia’s team with rats did not allow the researchers to identify the same harmful properties found in the studies with cell cultures.

There seems to be two reasons why in vivo studies do not show the same damaging effects of in vitro tests. First, what one calls the biodisposability of curcumin, the capacity of the body to absorb it, is fairly low. This means that the doses administered by Lusânia’s group to animals may have been too low to have any damaging effects. Second, in the body, curcumin is metabolized in the intestines, even before it enters the bloodstream; then it is metabolized again in the liver. This system presumably protects the latter from an eventual overdose of this substance.

Given these doubts, the team is returning to their lab benches in 2010 to create an in vitro model closer to what one observes in vivo. “We’re beginning the study with cells that are able to conduct this metabolization; this should allow us to better compare the results [of in vitro work with in vivo work]”, explains Lusânia. If these effects turn out to be successful, then it should be possible to begin speculating what might be the maximum safe dosage for oral ingestion in humans. Today, studies only show that more than a given amount of curcumin is bad for you. However, as almost all the tests were conducted in vitro, they do not allow us to calculate the dosage that poses a threat to the organism. This is the case because ingesting a few grams of curcumin results in very low concentrations of the compound in the blood. This concentration is measured in nanograms, far less than the amount to which cells will be submitted in the lab. The group also plans to investigate which genes are activated by curcumin and which are deactivated within the cells, in an attempt to elucidate the molecular mechanism behind such diverse effects.

If, on one hand, the issue of dosage and toxicity are worrisome, on the other hand some studies, conducted by people of various nationalities, including Brazilians, show encouraging results from using curcumin against certain types of cancer.

The group of urologist Miguel Srougi, from the Medical School of USP, has been working on the possibility of using curcumin against prostate and bladder tumors. In lab culture cells, they observed an impressive performance: curcumin drove the tumor cells to suicide by activating apoptosis, i.e., self-induced cell death. The results are particularly surprising, since tumors are generally formed by cells that have suffered mutations and that refuse to die, multiplying furiously.

Localized action
In the bladder cancer study, the São Paulo team went further: it conducted a series of in vivo experiments on mice. The tests showed a localized effect against cancer cells, with no collateral damage to the animals. “It is part of our plan to carry out, in the near future, clinical trials with curcuma against bladder cancer, possibly to be used as a second line of treatment”, explains Kátia Leite, a researcher in the group headed by Srougi.

The advantage of bladder tumors is that it is easy to apply curcumin directly. One can inject it straight into the bladder, via the urethra, so that the concentrations that reach the tumor are sufficient to affect it. When curcumin is administered orally, this becomes harder, given the body’s low capacity to absorb it. This finding helps to explain why many researchers say that people should not become too enthusiastic about including curcumin in their diet for its potential medicinal effects.

However, once again, not even as a drug for specific use and with controlled dosage is curcumin a solution for all evils. A study conducted by Mark Miller, an American from Wake Forest University, and presented in November 2009 at a congress in the town of Ouro Preto (inner-state Minas Gerais), showed that in tests against lung cancer conducted with genetically modified mice, curcumin made the illness worse, rather than fighting it.

The challenge now facing us is to decipher precisely how curcumin acts upon the organism, to understand why in can be good in some cases and bad in others. “We’re still a long way off from understanding exactly how curcumin works”, explains Kátia. “To achieve this, we will still need many more studies.”

The project
Neurotoxicity induced by the chemotherapic drug cisplatin: possible cytoprotective effects of antioxidants of the coenzyme Q10 and curcumin diet (nº 2008/53947-7); Type Regular Research Awards; Coordinator Lusânia Maria Greggi Antunes – USP-RP; Investment R$ 117,914.06

Scientific articles
MENDONÇA, L.M. et al. Evaluation of the cytotoxicity and genotoxicity of curcumin in PC12 cells. Mutation Research. v. 675, p. 29-34. 2009.
LEITE, K.R.M. et al. Effects of curcumin in an orthotopic murine bladder tumor model. International Brazilian Journal of Urology. v. 35, p. 599-607. Set./Out. 2009.