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Linus Pauling Institute

Micronutrient Research for Optimum Health

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Chlorophyll and Chlorophyllin

Summary Chlorophyll a and chlorophyll b are natural, fat-soluble chlorophylls found in plants. (More Information) Chlorophyllin is a semi-synthetic mixture of water-soluble sodium copper salts derived from chlorophyll. (More Information) Chlorophyllin 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 chlorophyllin form 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 chlorophyllin 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 chlorophyllin 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 chlorophyllin 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. Two different types of chlorophyll (chlorophyll a and chlorophyll b) are found in plants (structures of natural chlorophylls). The small difference in one of the side chains allows each type of chlorophyll to absorb light at slightly different wavelengths. Chlorophyllin is a semi-synthetic mixture of sodium copper salts derived from chlorophyll (2, 3). During the synthesis of chlorophyllin, the magnesium atom at the center of the ring is replaced with copper and the phytol tail is lost. Unlike natural chlorophyll, chlorophyllin is water-soluble. Although the content of different chlorophyllin mixtures may vary, two compounds commonly found

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in commercial chlorophyllin mixtures are trisodium copper chlorin e6 and disodium copper chlorin e4 (structures of two commercial chlorophyllins). Metabolism and Bioavailability Little is known about the bioavailability and metabolism of chlorophyll or chlorophyllin. The lack of toxicity attributed to chlorophyllin led to the belief that it was poorly absorbed (4). However, significant amounts of copper chlorin e4 were measured in the plasma of humans taking chlorophyllin tablets in a controlled clinical trial, indicating that it is absorbed. More research 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 chlorophyllin are able to form tight molecular complexes with certain chemicals known or suspected to cause cancer, including polycyclic aromatic hydrocarbons found in tobacco smoke (5), some heterocyclic amines found in cooked meat (6), and aflatoxin-B1 (7). See a computer-generated molecular model of a chlorophyllin-aflatoxin-B1 complex. The binding of chlorophyll or chlorophyllin to these potential carcinogens may interfere with gastrointestinal absorption of potential carcinogens, reducing the amount that reaches susceptible tissues (8). A recently completed study by Linus Pauling Institute investigator Professor George S. Bailey showed that chlorophyllin and chlorophyll were equally effective at blocking uptake of aflatoxin-B1 in humans, using accelerator mass spectrometry to track an ultra-low dose of the carcinogen (C Jubert et al., manuscript submitted). Antioxidant Effects Chlorophyllin can neutralize several physically relevant oxidants in vitro (9, 10), and limited data from animal studies suggest that chlorophyllin supplementation may decrease oxidative damage induced by chemical carcinogens and radiation (11, 12). 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 chlorophyllin may decrease the activity of cytochrome P450 enzymes (5, 13). Phase II biotransformation enzymes promote the elimination of potentially harmful toxins and carcinogens from the body. Limited data from animal studies indicate that chlorophyllin may increase the activity of the phase II enzyme, quinone reductase (14). Therapeutic Effects A recent study showed that human colon cancer cells undergo cell cycle arrest after treatment with chlorophyllin (15). 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 (15). This provides a potential new avenue for chlorophyllin in the clinical setting, sensitizing cancer cells to DNA damaging agents. Disease Prevention

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Aflatoxin-Associated Liver Cancer Aflatoxin-B1 (AFB1) a liver carcinogen produced by certain species of fungus, is found in moldy grains and legumes, such as corn, peanuts, and soybeans (2, 8). 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 chlorophyllin at the same time as dietary AFB1 exposure significantly reduces AFB1-induced DNA damage in the livers of rainbow trout and rats (16-18), and dose-dependently inhibits the development of liver cancer in trout (19). One rat study found that chlorophyllin did not protect against aflatoxin-induced liver damage when given after tumor initiation (20). In addition, a recent study reported that natural chlorophyll inhibited AFB1-induced liver cancer in the rat (18). 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 chlorophyllin supplementation can reduce the incidence of hepatocellular carcinoma in people exposed to high 7 levels of dietary AFB1. However, a biomarker of AFB1-induced DNA damage (AFB1-N -guanine) can 7 be measured in the urine, and high urinary levels of AFB1-N -guanine have been associated with significantly increased risk of developing hepatocellular carcinoma (21). 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 (22). Participants took either 100 mg of chlorophyllin or 7 a placebo before meals three times daily. After 16 weeks of treatment, urinary levels of AFB1-N guanine were 55% lower in those taking chlorophyllin than in those taking the placebo, suggesting that chlorophyllin supplementation before meals can substantially decrease AFB1-induced DNA damage. Although a reduction in hepatocellular carcinoma has not yet been demonstrated in humans taking chlorophyllin, scientists are hopeful that chlorophyllin supplementation will provide some protection to high-risk populations with unavoidable, dietary AFB1 exposure (8). For more information about the Chlorophyllin Clinical Trial, see Dr. George Baileys article in the Fall/Winter 2002 Linus Pauling Institute Newsletter. It is not known whether chlorophyllin 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 U.S. Many questions remain to be answered regarding the exact mechanisms of cancer prevention by chlorophyllin, the implications for the prevention of other types of cancer, and the potential for natural chlorophylls in the diet to provide cancer protection. Scientists from the Linus Pauling Institutes Cancer Chemoprotection Program (CCP) are actively pursuing these research questions. For more information about the CCP, see Dr. David Williams' article in the Spring/Summer 1999 Linus Pauling Institute Newsletter and the more recent update by Dr. Rod Dashwood in the Fall/Winter 2003 Linus Pauling Institute Research Report. Therapeutic Uses of Chlorophyllin Internal Deodorant Observations in the 1940s and 1950s that topical chlorophyllin had deodorizing effects on foulsmelling wounds led clinicians to administer chlorophyllin orally to patients with colostomies and ileostomies in order to control fecal odor (23). While early case reports indicated that chlorophyllin doses of 100-200 mg/d were effective in reducing fecal odor in ostomy patients (24, 25), at least one placebo-controlled trial found that 75 mg of oral chlorophyllin three times daily was no more effective than placebo in decreasing fecal odor assessed by colostomy patients (26). Several case reports have been published indicating that oral chlorophyllin (100-300 mg/day) decreased

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subjective assessments of urinary and fecal odor in incontinent patients (23, 27). Trimethylaminuria is a hereditary disorder characterized by the excretion of trimethylamine, a compound with a fishy or foul odor. A recent study in a small number of Japanese patients with trimethylaminuria found that oral chlorophyllin (60 mg three times daily) for three weeks significantly decreased urinary trimethylamine concentrations (28). Wound Healing Research in the 1940s indicating that chlorophyllin slowed the growth of certain anaerobic bacteria in the test tube and accelerated the healing of experimental wounds in animals led to the use of topical chlorophyllin solutions and ointments in the treatment of persistent open wounds in humans (29). 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 chlorophyllin promoted healing more effectively than other commonly used treatments (30, 31). In the late 1950s, chlorophyllin 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 (23). Chlorophyllin-containing papain/urea ointments are still available in the U.S. by prescription (32). Several studies have reported that such ointments are effective in wound healing (33). Recently, a spray formulation of the papain/urea/chlorophyllin therapy has become available (34). Sources Chlorophylls Chlorophylls are the most abundant pigments in plants. Dark green, leafy vegetables like spinach are rich sources of natural chlorophylls. The chlorophyll contents of selected vegetables are presented in the table below (35). Chlorophyll Content of Selected Raw Vegetables Food Spinach Parsley Cress, garden Green beans Arugula Leeks Endive Sugar peas Chinese cabbage Serving 1 cup cup 1 cup 1 cup 1 cup 1 cup 1 cup 1 cup 1 cup Chlorophyll (mg) 23.7 19.0 15.6 8.3 8.2 7.7 5.2 4.8 4.1

Supplements Chlorophyll Green algae like chlorella are often marketed as supplemental sources of chlorophyll. Because natural chlorophyll is not as stable as chlorophyllin and is much more expensive, most over-thecounter chlorophyll supplements actually contain chlorophyllin.

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Chlorophyllin Oral preparations of sodium copper chlorophyllin (also called chlorophyllin copper complex) are available in supplements and as an over-the-counter drug (Derifil) used to reduce odor from colostomies or ileostomies or to reduce fecal odor due to incontinence (36). Sodium copper chlorophyllin may also be used as a color additive in foods, drugs, and cosmetics (37). Oral doses of 100-300 mg/day in three divided doses have been used to control fecal and urinary odor (see Therapeutic Uses of Chlorophyllin). 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 (8, 23, 29). When taken orally, chlorophyllin may cause green discoloration of urine or feces, or yellow or black discoloration of the tongue (38). There have also been occasional reports of diarrhea related to oral chlorophyllin use. When applied topically to wounds, chlorophyllin has been reported to cause mild burning or itching in some cases (39). Oral chlorophyllin may result in false positive results on guaiac card tests for occult blood (40). 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. References Written 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 Reviewed in June 2009 by: Roderick H. Dashwood, Ph.D. Director, Cancer Chemoprotection Program, Linus Pauling Institute Professor of Environmental & Molecular Toxicology Leader, Environmental Mutagenesis & Carcinogenesis Core, Environmental Health Sciences Center Oregon State University Copyright 2004-2012 Linus Pauling Institute Disclaimer The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional. The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.

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