Chlorophyll and Metallo-Chlorophyll Derivatives

Summary

  • Chlorophyll a and chlorophyll b are natural, fat-soluble chlorophylls found in plants. (More information)
  • Sodium copper chlorophyllin (SCC) is a semi-synthetic mixture of water-soluble sodium copper salts derived from chlorophyll. (More information)
  • SCC has been used orally as an internal deodorant and topically in the treatment of slow-healing wounds for more than 50 years without any serious side effects. (More information)
  • Chlorophylls and SCC form tight molecular complexes with some chemicals known or suspected to cause cancer, and in doing so, may block carcinogenic effects. Carefully controlled studies have not been undertaken to determine whether a similar mechanism might limit uptake of required nutrients. (More information)
  • Supplementation with SCC before meals substantially decreased a urinary biomarker of aflatoxin-induced DNA damage in a Chinese population at high risk of liver cancer due to unavoidable, dietary aflatoxin exposure from moldy grains and legumes. (More information)
  • Scientists are hopeful that SCC supplementation will be helpful in decreasing the risk of liver cancer in high-risk populations with unavoidable, dietary aflatoxin exposure. However, it is not yet known whether SCC or natural chlorophylls will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary aflatoxin. (More information)

Introduction

Chlorophyll is the pigment that gives plants and algae their green color. Plants use chlorophyll to trap light needed for photosynthesis (1). The basic structure of chlorophyll is a porphyrin ring similar to that of heme in hemoglobin, although the central atom in chlorophyll is magnesium instead of iron. The long hydrocarbon (phytol) tail attached to the porphyrin ring makes chlorophyll fat-soluble and insoluble in water. Chlorophyll a and chlorophyll b represent about 99% of the chlorophyll species found in edible plants (Figure 1; 2), while some algae and microalgae contain minor quantities of chlorophyll c pigments (e.g., Laminaria ochroleuca, Undaria pinnatifida) (3). Chlorophyll a and b only have a small difference in one of the side chains but an intact phytol tail, while the common characteristic of chlorophyll c isoforms is the absence of a phytol tail. These structural differences cause each type of chlorophyll to absorb light at slightly different wavelengths.

Metallo-chlorophyll derivatives, including chlorophyllins, can be chemically synthesized or produced in industrial food processing; these compounds contain zinc, iron, or copper in place of the central magnesium atom (2). The most studied chlorophyllin, sodium copper chlorophyllin (SCC), is a semi-synthetic mixture of sodium copper salts derived from chlorophyll (4, 5). SCC is often simply called ‘chlorophyllin’ in the older scientific literature, with newer publications specifying whether iron, zinc, copper, or magnesium chlorophyllin were studied. During its synthesis, the magnesium atom at the center of the ring is replaced with copper (or other metals), and the phytol tail is lost. Unlike natural chlorophyll, chlorophyllins (regardless of the metal used) are water-soluble. Although the content of different SCC mixtures may vary, two compounds commonly found in commercial SCC are trisodium copper chlorin e6 and disodium copper chlorin e4 (Figure 2).

Figure 1. Chemical structures of natural chlorophylls: chlorophyll a and chlorophyll b.

Figure 2. Chemcical structures of two compounds found in commercial sodium copper chlorophyllin: trisodium copper chlorin e6 and disodium copper chlorin e4.

Metabolism and Bioavailability

Little is known about the bioavailability and metabolism of chlorophyll in humans, although it is known that chlorophyll undergoes extensive metabolism once consumed. Animal model studies show only about 1%-3% of chlorophyll is absorbed, while the rest is excreted in the feces, primarily as pheopytin and pyropheophytin metabolites, indicating that significant transformation and microbial metabolism occur in the gastrointestinal tract (reviewed in 2). A recent study in eight healthy adults found pheophytin and pheophorbide derivatives in the blood of most subjects following consumption of 1.2 kg boiled spinach, a concentrated source of chlorophyll (6).

Sodium copper chlorophyllin was originally thought to be poorly absorbed because of its lack of apparent toxicity. However, a placebo-controlled clinical trial found that significant amounts of copper chlorin e4 in the serum of people taking chlorophyllin tablets (300 mg/day) (7), indicating that it is indeed absorbed. In vitro studies have found chlorin e4 to have a higher stability than chlorin e6 (2).

More research, however, is needed to understand the bioavailability and metabolism of natural chlorophylls and chlorin compounds in synthetic chlorophyllin.

Biological Activities

Complex formation with other molecules

Chlorophyll and sodium copper chlorophyllin are able to form tight molecular complexes with certain chemicals known or suspected to cause cancer, including polyaromatic hydrocarbons found in tobacco smoke (8), some heterocyclic amines found in cooked meat (9), and aflatoxin-B1 (10). The binding of chlorophyll or SCC to these potential carcinogens may interfere with gastrointestinal absorption of potential carcinogens, reducing the amount that reaches susceptible tissues (11). This has been demonstrated in humans: a cross-over study in three volunteers that used accelerator mass spectrometry to study the pharmacokinetics of an ultra-low dose of aflatoxin-B1 found a 150-mg dose of either SCC or chlorophyll could decrease absorption of aflatoxin-B1 (12).

Antioxidant effects

SCC can neutralize several physically relevant oxidants in vitro (13-16), and limited data from animal studies suggest that SCC supplementation may decrease oxidative damage induced by chemical carcinogens and radiation (17, 18). While chlorophyll and its derivatives have demonstrated antioxidant activity in in vitro assays (15, 19), the relevance of these findings to humans is not clear.

Modification of the metabolism and detoxification of carcinogens

To initiate the development of cancer, some chemicals (procarcinogens) must first be metabolized to active carcinogens that are capable of damaging DNA or other critical molecules in susceptible tissues. Since enzymes in the cytochrome P450 family are required for the activation of some procarcinogens, inhibition of cytochrome P450 enzymes may decrease the risk of some types of chemically induced cancers. In vitro studies indicate that SCC may decrease the activity of cytochrome P450 enzymes (8, 20, 21). Phase II biotransformation enzymes promote the elimination of potentially harmful toxins and carcinogens from the body. Limited data from animal studies indicate that SCC may increase the activity of the phase II enzyme quinone reductase (22).

Therapeutic effects

One in vitro study showed that human colon cancer cells undergo cell cycle arrest after treatment with SCC (23). The mechanism involved inhibition of ribonucleotide reductase activity. Ribonucleotide reductase plays a pivotal role in DNA synthesis and repair and is a target of currently used cancer therapeutic agents, such as hydroxyurea (23). While this may provide a potential avenue for SCC in the clinical setting, sensitizing cancer cells to DNA damaging agents, in vivo studies are needed.

Metal absorption

The porphyrin structure of chlorophyll is analogous to the heme structure found in blood and muscle tissue. Because heme-bound iron has higher bioavailability than nonheme iron (the most common form of iron in plant-based sources, e.g., legumes, spinach), iron uptake from iron chlorophyll is of interest. Toxicity studies in rats suggest iron chlorophyllin is generally safe for mammalian consumption (24). In vitro studies demonstrate that iron chlorophyllin is as good as heme in delivering iron to intestinal cells, and significantly better than the most common supplemental form of iron (i.e., ferrous sulfate) when incorporated into most food matrices (25). However, work in this area is nascent and has not yet been validated in humans. It is also not known if metallo-chlorophyll derivatives of copper or zinc increase absorption of these essential divalent metals.

Disease Prevention

Aflatoxin-associated liver cancer

Aflatoxin-B1 (AFB1), a liver carcinogen produced by certain species of fungus, is found in moldy grains and legumes, including corn, peanuts, and soybeans (4, 11). In hot, humid regions of Africa and Asia with improper grain storage facilities, high levels of dietary AFB1 are associated with increased risk of hepatocellular carcinoma. Moreover, the combination of hepatitis B infection and high dietary AFB1 exposure increases the risk of hepatocellular carcinoma still further. In the liver, AFB1 is metabolized to a carcinogen capable of binding DNA and causing mutations. In animal models of AFB1-induced liver cancer, administration of SCC at the same time as dietary AFB1 exposure significantly reduces AFB1-induced DNA damage in the livers of rainbow trout and rats (26-28) and dose-dependently inhibits the development of liver cancer in trout (29). Likewise, natural chlorophyll has also been found to inhibit AFB1-induced liver cancer in the rat (28). Collectively, this evidence supports a role for SCC and/or chlorophyll itself in limiting cancer initiation. In contrast, data suggest a limited role for SCC in influencing cancer progression. For example, one rat study found that SCC did not protect against aflatoxin-induced liver damage when given after tumor initiation (30).

Because of the long time period between AFB1 exposure and the development of cancer in humans, an intervention trial might require as long as 20 years to determine whether SCC supplementation can reduce the incidence of hepatocellular carcinoma in people exposed to high levels of dietary AFB1. However, a biomarker of AFB1-induced DNA damage (AFB1-N7-guanine) can be measured in the urine, and high urinary levels of AFB1-N7-guanine have been associated with significantly increased risk of developing hepatocellular carcinoma (31). In order to determine whether chlorophyllin could decrease AFB1-induced DNA damage in humans, a randomized, placebo-controlled intervention trial was conducted in 180 adults residing in a region in China where the risk of hepatocellular carcinoma is very high due to unavoidable, dietary AFB1 exposure and a high prevalence of chronic hepatitis B infection (32). Participants took either 100 mg of SCC or a placebo before meals three times daily. After 16 weeks of treatment, urinary levels of AFB1-N7-guanine were 55% lower in those taking SCC than in those taking the placebo, suggesting that SCC supplementation before meals can substantially decrease AFB1-induced DNA damage. Although a reduction in hepatocellular carcinoma has not yet been demonstrated in humans taking SCC, scientists are hopeful that supplementation will provide some protection to high-risk populations with unavoidable, dietary AFB1 exposure (11).

It is not known whether SCC will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary AFB1, as is the case for most people living in the US. Many questions remain to be answered regarding the exact mechanisms of cancer prevention by SCC, the implications for the prevention of other types of cancer, and the potential for natural chlorophylls in the diet to provide cancer protection.

Therapeutic Uses of Chlorophyllin

Internal deodorant

Observations in the 1940s and 1950s that topical SCC had deodorizing effects on foul-smelling wounds led clinicians to administer SCC orally to patients with colostomies and ileostomies in order to control fecal odor (33). While early case reports indicated that SCC doses of 100 to 200 mg/day were effective in reducing fecal odor in ostomy patients (34, 35), a placebo-controlled trial found that 75 mg of oral SCC three times daily was no more effective than placebo in decreasing fecal odor assessed by colostomy patients (36). Several case reports have been published indicating that oral SCC (100-300 mg/day) decreased subjective assessments of urinary and fecal odor in incontinent patients (33, 37).

Trimethylaminuria is a hereditary disorder characterized by the excretion of trimethylamine, a compound with a “fishy” or foul odor. One study in a small number of Japanese patients with trimethylaminuria found that oral SCC (60 mg three times daily) for three weeks significantly decreased urinary trimethylamine concentrations (38).

Wound healing

Research in the 1940s indicated that chlorophyllin slowed the growth of certain anaerobic bacteria in the test tube and accelerated the healing of experimental wounds in animals. These findings led to the use of topical SCC solutions and ointments in the treatment of persistent open wounds in humans (39). During the late 1940s and 1950s, a series of largely uncontrolled studies in patients with slow-healing wounds, such as vascular ulcers and pressure (decubitus) ulcers, reported that the application of topical SCC promoted healing more effectively than other commonly used treatments (40, 41). In the late 1950s, SCC was added to papain and urea-containing ointments used for the chemical debridement of wounds in order to reduce local inflammation, promote healing, and control odor (33). SCC-containing papain/urea ointments are still available in the US by prescription (42). Several studies have reported that such ointments are effective in wound healing (43). A spray formulation of the papain/urea/SCC therapy is also available (44).

Skin conditions

A few small studies have investigated SCC as a topical treatment for various skin conditions. In a pilot study of 10 adults (ages 18-30 years) who had mild-to-moderate acne vulgaris and enlarged facial pores, twice daily application of a 0.1% liposomal SCC gel for three weeks improved a number of clinical parameters of the Global Acne Assessment Scale (i.e., facial oiliness, facial blotchiness, presence and size of facial pores, and number of acne lesions) compared to baseline (45). Additionally, a pilot study in 10 women (ages 40 years or older) with noticeable photodamage and solar lentigines found that twice daily topical application of a gel containing 0.66% SCC complex salts for eight weeks improved various clinical measures, including tactile and visual roughness of facial skin, skin radiance, fine lines, pore size, and overall photodamage (46). A few case reports have also observed some improvement in facial redness and rosacea with application of topical SCC (47).

While the reports from these studies are interesting, placebo-controlled clinical trials are needed to determine whether SCC may have utility in treating various skin conditions.

Sources

Chlorophylls

Chlorophylls are the most abundant pigments in plants, with chlorophyll a being two to four times as prevalent as chlorophyll b (6, 48). Dark-green leafy vegetables like spinach are rich sources of natural chlorophylls. The chlorophyll content of selected vegetables are presented in Table 1 (49).

Table 1. Chlorophyll Content of Selected Raw Vegetables
Food Serving Chlorophyll (mg)
Spinach 1 cup 23.7
Parsley ½ cup 19.0
Cress, garden 1 cup 15.6
Green beans 1 cup 8.3
Arugula 1 cup 8.2
Leeks 1 cup 7.7
Endive 1 cup 5.2
Sugar peas 1 cup 4.8
Chinese cabbage 1 cup 4.1

Food and supplements

Chlorophyll

Green algae like chlorella are often marketed as supplemental sources of chlorophyll. Because natural chlorophyll is not as stable as SCC and is much more expensive, most over-the-counter chlorophyll supplements actually contain sodium copper chlorophyllin.

Sodium copper chlorophyllin

Oral preparations of sodium copper chlorophyllin (also called chlorophyllin copper complex) are available as a dietary supplement and as an over-the-counter drug (Derifil) used to reduce odor from colostomies and ileostomies, or to reduce fecal odor due to incontinence (50). Oral doses of 100 to 300 mg/day in three divided doses have been used to control fecal and urinary odor (see Therapeutic Uses of Chlorophyllin).

In the US, SCC is found in minor quantities in some types of green table olives (51). It is also approved for use as a green color additive in a limited number of foods like chewing gum (52), as well as in drugs and cosmetics, as detailed in the Code of Federal Regulations 21 (53).

Zinc chlorophyll derivatives

In US supermarkets, canned green beans thermally processed in a zinc chloride solution to produce zinc chlorophyll derivatives within the green beans themselves are sold under the trademarked name "veri-green" (54). Because zinc chlorophyll derivatives are more robust to heat and acid treatment, they better retain a bright green color as compared to native magnesium-bound chlorophyll (48).

Safety

Natural chlorophylls are not known to be toxic, and no toxic effects have been attributed to chlorophyllin despite more than 50 years of clinical use in humans (11, 33, 39). When taken orally, supplemental chlorophyll or sodium copper chlorophyllin may cause green discoloration of urine or feces, or yellow or black discoloration of the tongue (55). There have also been occasional reports of diarrhea related to oral SCC use. When applied topically to wounds, SCC has been reported to cause mild burning or itching in some cases (56). Oral chlorophyllin may result in false positive results on guaiac card tests for occult blood (57). Since the safety of chlorophyll or chlorophyllin supplements has not been tested in pregnant or lactating women, they should be avoided during pregnancy and lactation.


Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2022 by:
Rachel E. Kopec, Ph.D.
Assistant Professor of Human Nutrition
The Ohio State University

Copyright 2004-2022  Linus Pauling Institute


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