Phenolic Acids

Plant polyphenols are known for their positive effects on human health. Considerable amounts of flavonoids, a class of polyphenols having rather large molecules, are present in higher amounts in many fruits and other foods of plant origin. They are poorly absorbed from the intestine limiting their bioavalability and positive effects on human health. However, they also undergo considerable transformation by intestinal microflora and various products of degradation may be formed during the digestion, absorption, and metabolic processes in the gastrointestinal tract. Phenolic acids (PA) are a type of organic compounds much smaller and simpler in structure than flavonoids. Included in that class are substances containing a phenolic ring and an organic carboxylic acid function (C6-C1 skeleton).

Phenolic acids are formed by plants as secondary metabolites, meaning not essential for growth, development, or reproduction, and are widely spread throughout the plant kingdom. There are many different types of phenolic acids. Some of the common ones are gallic, chlorogenic, benzoic, coumaric, caffeic, ellagic and ferulic acids and their derivatives. Phenolic acids are among the major end products of flavonoids or other polyphenol metabolism by the intestinal microbes.

Recent interest in phenolic acids stems from their potential protective role, through ingestion of fruits and vegetables, against oxidative damage diseases (coronary heart disease, stroke, and cancers). For instance, ferulic acid (4-hydroxy-3-methoxycinnamic acid) has been shown to reduce hypertension, lipid peroxidation, oxidative impairments, and enhance insulin secretion in rats, while p-methoxycinnamic acid has been found to stimulate insulin secretion from the pancreatic β-cells in rats. Caffeic acid has been shown to improve glucose utilization and reduce plasma glucose in diabetic rats, while chlorogenic acid attenuates hypertension and endothelial cell function in spontaneously hypertensive rats. Similarly, O-coumaric acid was found to be effective in improving the symptoms of metabolic syndrome and obesity. 3,4-dihydroxybenzoic acid (also known as protocatechuic acid) is another PA found in many edible and medicinal plants. It is a major metabolite of cyanidin-3-glucoside, an anthocyanin, metabolism and has been shown to have many health effects, including chemoprevention and improvement of antioxidant status; a major factor involved in many of the chronic diseases.

Presence of large amounts of monophenolic acids have been demonstrated previously in the colon of healthy humans. While the absorption of flavonoids and other large molecular weight polyphenols may be poor, PA can be absorbed into the circulation and may contribute to the health-promoting effects. Moreover, PA or their metabolic products may actually be the active compounds responsible for at least some of the health promoting effects associated with their parent compounds. However, the extent and importance of absorption of many of these PA is not known.

Parent flavonoids in the diet are often deglycosylated before absorption and are also conjugated by methylation, glucuronidation, sulfation, etc. during the absorption process. They are usually excreted through the urine, while extensively conjugated ones may also find their in the bile. While many studies have reported free or total PA, little is known about their conjugated counterparts. Since PA and other metabolites formed by the intestinal microflora and/or those produced in host tissues are excreted in the urine, it is imperative to identify and quantify the PA excreted in urine after ingestion of plant polyphenols. Therefore, measurement of just the free form may not accurately reflect the amount excreted, and studies investigating the health effects, bioactivity, or bioavailability of parent polyphenols should also consider their metabolites, like phenolic acids and their derivatives, not just the parent compound(s).

Overall, research on the effects of PAs for improving human health or their mechanism of action is in its infancy. Given that plant polyphenols are widely believed and extensively studied for their numerous health benefits, it is not difficult to surmise some positive effects for PAs as well. However, this by no means indicates a definite answer for any of the health maladies we face as individuals.

Conjugated linoleic acid and cancer

Fats in general have been implicated in the etiology of many forms of cancer, yet evidence is accumulating that certain types of fatty acids have anticancer properties, of which conjugate linoleic acd (CLA) is the major one. Inhibitory effects of CLA against carcinogenesis have been demonstrated in a variety of cell type, sites, and animal models including mammary gland, skin, colon, prostate, and forestomach of rats, humans, mice, and hamsters. In contrast to the hundreds of phytochemicals possessing varying degrees of anticancer properties, CLA is unique in that it is a FA, is found in highest amounts in food products derived from ruminants, and is safe at dietary levels. It is believed that CLA is involved in a variety of biological events in all three stages of carcinogenesis viz initiation, promotion, and progression. It is also believed that the effects vary with the specific isomers of CLA and the type and site of the cell/organ as well as the stage of tumerogenesis. Overall, the effects of CLA are related to inhibition of growth and proliferation, induction of apoptosis, and diminishing branching and reducing the density of ductal system of the cancerous cells.

It was found that mammary tumor incidence as well as mass and weight were reduced in rats fed CLA. Exposure to 1% CLA during the early preweaning and pubertal period only was sufficient to reduce the subsequent methylnitrosurea induced tumerogenesis in rats, which may have further implications in cancer prevention in humans once it is proven with clinical case-control studies. It has also been found that CLA decreased mammary tumor incidence by 50% and tumor number by 45% in rats fed CLA at 0.8% of the diet. By way of comparison, the efficacy of fish oil, which is also an anticancer agent and which is not plant derived, is 100 times lower than that of CLA. It was found that cell number was decreased up to 90% and lipid peroxidation increased by 15-fold following incubation of breast cancer cells for 8 days with increasing levels of milk, yielding CLA concentrations between 16.9 and 22.6 ppm. Moreover, CLA has not only been found altering mammary tumor incidence, but also affecting later stages, especially metastasis as effectively as indomethacin, a known suppressor of tumor growth and metastasis in murine mammary tumors. It supports the notion that CLA may be efficacious in preventing the development and recurrence of some cancers as well as suppressing the growth of residual disease. 

There are many different isomers of CLA, of which t-10, c-12 CLA and c-9, c-11 CLA are the major ones. Using an apoptotic marker, c-9, t-11 CLA was found to be the better apoptotic inducer compared with t-10, c-12 or a mixture of c-9, t-11 CLA and t-10, c-12 isomers both in breast cancer cell lines. This is in contrast to some other findings on colorectal and prostate cancer cells where t-10, c-12 CLA led to an apoptotic response. In another experiment, c-9, t-11 CLA also turned out to be the best radiosensitizer compared with t-10, c-12 or a mixture of c-9, t-11 CLA and t-10, c-12 isomers. The radiosensitizing property of c-9, t-11 CLA further supports its potential as an agent to improve radiotherapy against breast carcinoma. Regardless, the effects of specific isomer(s) of CLA responsible for anticancer properties are not conclusive nor their mode of action has been well understood.

Plant polyphenols and human health

Plant polyphenols are a group of compounds found in many plants and their parts with several hydroxyl groups on aromatic ring, also known as phenol, structures.  They are the secondary plant metabolites, meaning the substances that have little or no role in photosynthesis, respiration, or growth and development, but which may accumulate in surprisingly high concentrations. They usually provide protection to plants against many herbivores and microbes. They also provide color, taste (such as bitter, tart, astringent, and more), and structural rigidity and strength (with lignin) to plants and their parts, such as the fruits, vegetables, seeds, bran, bark, pulp, juice, nectar, and more. Some of the well known plant polyphenolics are tannins, lignins, lignans, anthocyanins, quercetin, and resveratrol, among others. While lignin is the most abundant phenolics in nature, condensed tannins (also known as proanthocyanidins) are also ubiquitously present in virtually all families of plants, and may comprise up to 35% of the dry weight of certain leaves.

Polyphenols were initially and are often considered antinutrients, compounds that interfere with the absorption of other nutrients, such as protein, as a mechanism of plant defense against herbivores. While it is true, many of the polyphenolics or phytochemicals are equally beneficial for our health and nutrition. Unlike the traditional vitamins, phytochemicals as dietary components are not essential for short term well-being. While our body has specific mechanisms for the accumulation and retention of vitamins, most of the phytochemicals are treated as non-nutrient xenobiotics and metabolized so as to eliminate them efficiently. Regardless, they are high in antioxidants and accord protection against oxidative stress in our daily lives. 

Interest in plant polyphenols have increased tremendously over the past several years. Numerous studies are conducted each year to elucidate the effect, actions, and mechanisms by which plant polyphenols exert protective health effects in humans. As a result, there is considerable evidence that diets rich in fruit and vegetables can reduce the incidence of non-communicable diseases of the chronic nature, such as diabetes, metabolic syndrome, cardiovascular disease, cancer, Alzheimer’s, and urinary tract disease, among others. Although most of the protective effects were initially attributed to their high antioxidant capacity and the resultant decrease in oxidative stress, research has emerged lately that they also exert modulatory effects on different components of the intracellular signaling pathways vital for such cellular functions as growth, proliferation and apopotosis.  

Several thousand polyphenols are known to be present in higher plants, while several hundred have been found in edible plants. The health effects of polyphenols depend on their type, amount consumed, bioavailability, and some other factors such as the physiological state and other foods that are consumed along with polyphenols. Some of the foods that are high in plant polyphenols include fruits, vegetables, spices, red wine, green tea, and cocoa etc. They are also present in other foods such as sorghum, millet, barley, dry beans, peas, black beans, and other legumes. Among the fruits, berries are high in polyphenols. Among the by-products, seeds, skins, and different types of bran contain high concentrations of polyphenols.

Conjugated Linoleic Acid (CLA): A beneficial fatty acid of ruminant origin

What is CLA?

The conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid, a fatty acid (or fat in plain English). CLAs have two conjugated (alternate) unsaturated double bonds at various carbon positions in the fatty acid chain. Each double bond can be a cis or trans, but those with one trans double bond are bioactive. CLAs are synthesized by the rumen microbes, primarily Butyrivibrio fibrisolvens, which is to say those present in the rumen of cows, sheep, goats, and buffaloes among the domestic animals.

Why is CLA important?

Ever since Ha and his coworkers¹ demonstrated that CLA obtained from fried ground beef inhibited carcinogenesis, a whole new era of research dedicated to CLA began. Thanks to thousands of reports, principally based on in vitro, microbial, animal and of late clinical trials on humans, CLA is now linked to have beneficial effects in obesity, diabetes, cardiovascular disease, cancer, and atherosclerosis. The CLA has also been shown to have immunomodulatory, apoptotic and osteosynthetic effects. More recently, FDA approved the CLA as Generally Recognized as Safe category so that it can be used in various food and beverages. This may open up yet another era on CLA research aimed at finding some important solutions to ever increasing problems of aforementioned chronic diseases. On the other hand, a few negative effects of CLA have also been reported, such as fatty liver and spleen, induction of colon carcinogenesis and hyperproinsulinemia. While a plethora of research have shown the positive effects of CLA in many experimental models, it is by no means a surefire finding in actual human beings under practical situations. Moreover, its mechanism of action is also not very clear. As a result, scientists are conducting numerous experiments every year to provide a definite answer as to the great positive effects of CLA in humans and its mode of action.

Where can CLA be found?

Since only the microbes present in the rumen are capable of actually synthesizing the CLA or its precursor trans-vaccenic acid, another type of fat, foods of ruminant origin are the primary sources of CLA for human consumption. However, milk or meat from animals grazed on fresh pastures has the highest concentrations of CLA (does it sound organic? I bet it does). Increasing the proportion of grass in animal diet would also help increase the CLA content in the milk or meat. However, milk or meat from animals fed large amounts of grains, such as those in the form of total mixed rations or beef fattening programs have the least amount of CLA. Trans-vaccenic acid can be converted into CLA in the mammary gland with the help of an enzyme, thus enhancing the overall CLA content of foods from ruminants.

¹Ha, Y. L., N. K. Grimm and M. W. Pariza. 1987. Anticarcinogens from fried ground beef: Heat-altered derivatives of linoleic

acid. Carcinogenesis. 8:1881-1887.