2.5 PRIMARY METABOLITES WITH THERAPEUTIC POTENTIAL
Ecological and evolutionary considerations are of much lesser importance to the occurrence of primary metabolites within the plant kingdom for the simple reason that primary metabolites are so essential for the functioning of all plants that they are ubiquitous and their functions in plant physiology are also well understood. Primary metabolites include carbohydrates, fats, proteins, vitamins, and the pigments involved in photosynthesis. These are, of course, of greatest importance to humans nutritionally, but some blur the line between nutrition and medicine and others appear to be useful as medicines in their own right, especially when artificially modified from their naturally occurring forms. The following is not an exhaustive list, as this is a recent and rapidly expanding field of research; we merely aim to highlight the concept of primary metabolites as sources of biologically active compounds with therapeutic potential. Here we showcase some particularly noteworthy recent examples that could provide cheap and abundant sources of anticancer, antiviral, and antibacterial drugs and even help against neurodegenerative disorders.
2.5.1 Pectin
Pectin is actually not a single substance but a complex macromolecule composed of a number of different types of “pectic polysaccharides” that together form a tangle of molecular strands. These are essential for the integrity and elasticity of the plant cell wall and perform the role of intercellular “glue,” bonding plant cells together to form tissues. While pectin is a component of all plants, fruits may have extremely high pectin contents, and citrus peel and the solid wastes from apple juice production are the main industrial sources of pectin. However, it can also be readily isolated from Sycamore (Acer pseudoplatanus) (Marfà et al., 1991) or red wine (Pellerin et al., 1996).
Pectin is an important form of dietary fiber, and as an emollient, it can ease the digestive tract and is used for anti-diarrhea treatment in the form of bismuth subsalicylate. However, pectin has recently revealed a new face. It has been discovered that while citrus pectin—a naturally occurring form found in the diet—has no anti-tumor properties, when a little heat is applied or the pH altered, the strands of pectin rearrange themselves to produce a different conformation. This modified citrus pec- tin interferes with cell-to-cell interactions mediated by cell surface molecules that bind to carbohydrates. This confers anticancer activity against rat and human pros- tate carcinomas (Pienta et al., 1995; Jackson et al., 2007), human breast carcinoma cells, and human colon carcinoma cells (Nangia-Makker et al., 2002) in vitro or when human cells are cultured in animals, but has yet to be tested in vivo in humans.
2.5.2 lignin
Lignin is another highly complex macromolecular component of cell walls, and we have seen that it is essential for the rigidity of stems and thus the ability of plants to grow in height. It is thus particularly common in woody plants, particularly in stems and other solid structures such as pine cones. Indeed, the main source of lignin for medicinal purposes is the wood of Japanese Cedar (Cryptomeria japonica), Japanese Beech (Fagus crenata), Rice husks (Oryza sativa), and Bamboo (Phyllostachys bam- busoides) (Akao et al., 2004). Certain lignins (to be precise, particular configurations of the highly complex lignin “network”) are known to have an activity against human immunodeficiency virus and cancerous cells (Akao et al., 2004, and references therein), but the tough nature of lignin and the mechanical processes that are used to extract it result in an inconsistent end product that is difficult to massproduce.
However, novel chemical methods of extracting lignins are being developed, using acids and phenols to extract lignin in the form of “lignophenols.” These lignin derivatives are known to protect human neurons, in vitro, against reactive oxygen species and, although this has yet to be tested in vivo, encouraging early results sug- gest that lignin could potentially find a therapeutic role in delaying the progress of neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (Akao et al., 2004).
2.5.3 Chlorophylls
Chlorophylls are of course pigments that are essential for the process of capturing light energy during photosynthesis. Being antioxidants, they are also a useful component of the human diet, but recently it has been found that naturally occurring chlorophylls and a chlorophyll derivative, sodium copper chlorophyllin (SCC), also confer a degree of protection against a range of cancer-causing agents in vitro (reviewed by Ferruzzi and Blakeslee 2007). Natural chlorophylls extracted from Spinach (Spinacia oleracea) and SCC both have proven ability to reduce mutagenic effects in vivo in Rainbow Trout livers (Harttig and Bailey, 1998), and a number of studies have shown that SCC is effective in vivo against skin cancer in mice (Ferruzzi and Blakeslee, 2007, and references therein). This appears to be a result not only of the antioxidant properties of chlorophyll but also of the ability to induce apoptosis, demonstrated for SCC acting on human hepatocellular carcinoma cells (Chan et al., 2006) and human colon cancer cells (Diaz et al., 2003). However, a range of positive and negative effects of natural chlorophylls and SCC has been observed for colon cancer in rats, and the particular combinations of chlorophyll form and dosage that are beneficial remain an unknown factor that currently hinders chlorophyll use as a drug.
We now know that the traditional view that the human gut does not absorb chlorophyll derivatives is flawed, as blood plasma of patients taking SCC supplements contains SCC-derived compounds, and gut cells have now been shown to absorb chlorophyll derivatives (Ferruzzi and Blakeslee, 2007). Further encouragement regarding the therapeutic potential of chlorophyll against human liver cancer in vivo comes from a randomized, double-blind, placebo-controlled trial in Qidong in China, where inhabitants are exposed to carcinogenic aflatotoxin B1. For four months, participants in the trial consumed supplements of 100 mg SCC three times daily, which resulted in a 55% reduction in aflatoxin-N7-guanine excreted in the urine. Ferruzzi and Blakeslee (2007) suggest that while this is heartening it might be simpler, and just as effective, to eat plenty of green vegetables.
2.5.4 Should primary mteabolites and their derivatives be regulated?
One perceived advantage of primary metabolites as medicines is that these compounds are an unavoidable part of every diet and have therefore been eaten by humans for the entire history of the species—they have an exemplary safety record and are usually exempt from regulation. However, artificially modified forms and derivatives, such as lignophenols, have never been a part of the human diet. Conversely, some derivatives of plant primary metabolites that have always been a part of human diets, such as alcohol, can undoubtedly incur health risks and are currently regulated. It may be wise to ask ourselves what the possible human health implications of primary metabolite derivatives are, and whether compounds that seem familiar, and for which it is intuitive to assume are benign, are truly trustworthy.
2.6 CONCLUSIONS
Throughout the plant kingdom, from the lowliest alga to the loftiest tree, there exist a vast diversity of biologically active compounds that originally evolved to defend algae, and then land plants, against herbivores, disease, or other competing plants. However, it has only recently become appreciated that the primary metabolites that all plants must produce for their basic functioning and growth can also provide a range of readily available biologically active compounds that could potentially be developed into relatively economical therapies even for some of the most pernicious human diseases.
Soure: Giacinto Bagetta, Marco Cosentino, Marie Tiziana Corasaniti, Shinobu Sakurada (2012); Herbal Medicines: Development and Validation of Plant-derived Medicines for Human Health; CRC Press
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