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Although various physiologically beneficial functions of tea catechins have been reported up until now, there is no compre- hensive study that reveals how tea catechins are absorbed, metabolized, and excreted qualitatively as well as quantita- tively. The compound (⫹)-catechin, which is a trace constit- uent and of the least physiological potency among tea cate- chins, has been examined in several reports by Griffiths et al. on the metabolic changes in animals (1) or in humans (2). After

oral intake, (⫹)-catechin was confirmed to be absorbed and

undergo methylation and conjugation in the liver and be ex- creted partly in the bile and mostly in the urine.

EGCg is quantitatively dominant and physiologically the most potent among tea catechins, and we traced its fate in the digestive tract of rats (3). Fifty mg of EGCg was administered orally to fasted rats; then 1, 2, 5, 8, 12, 16, and 20 hours there- after, residual content of EGCg in the stomach, small intes- tine, large intestine, as well as in the feces was determined.

FIG. 1 Residual EGCg in different sections of the digestive tract of rats administered 50 mg of EGCg.

As shown in Fig. 1, within a few hours after administration, the EGCg in the stomach disappeared rapidly and moved into the small intestine. The amount of EGCg in the large intestine began to increase sharply as the amount in the small intestine decreased, and was at its highest around eight hours after in- gestion, at which time only a trace amount remained in the other organs. EGCg appeared in the feces 12 hours after inges- tion and increased gradually thereafter. In the two hours after administration, when a small amount of EGCg was already in the large intestine, about 20% of the EGCg was lost (i.e., unrecoverable). We concluded that this 20% disappearance of EGCg is equivalent to the amount absorbed into the body through the small intestinal wall. This assumption is backed up by a previous report that confirms that EGCg does not un- dergo any degradation in the stomach or small intestine (3). Hattori et al. showed that when galloyl catechins (EGCg, ECg)

were incubated anaerobically with human feces, they succumb to extensive degradation, whereas they are stable in rats’ feces (4). The latter is, however, not likely in our experiment in rats with tritiated EGCg. There seems to be certain degradation of EGCg in rat’s large intestine. In the following experiments with rats, we have confirmed the absorption and existence of EGCg and other individual catechins in the portal vein (5). Forty-five minutes after administering each catechin orally, the portal blood was collected and each catechin was isolated and purified from the blood. Those purified compounds were identified as individual catechins by HPLC and LC/MS analy- ses. We have found by incubating catechins with methyl group donor, S-adenosyl-L-methionine, in rat liver homogenates that

O-methylation occurs at 4′ position of EGC or 4″ position in

galloyl moiety of ECg and EGCg as shown inFig. 2(6). After oral administration of (⫺)-epicatechin (EC) to rats, its metabo- lites and the fate of them were investigated (7). We identified 3′-O-methyl-EC, 4′-O-methyl-EC, EC-5-O-β-glucuronide and 3′-O-methyl-EC-5-O-β-glucuronide as metabolites of EC. In the urine, EC-conjugates were the major forms of EC metab- olites while in plasma and bile, 3′-O-methyl-EC-conjugates seemed to be dominant(Fig. 3).

More practically in humans, C. S. Yang et al. confirmed the presence and excretion of the glucuronide and/or sulfate of individual catechins in the plasma and urine of subjects who took 1.2 gram of decaffeinated green tea extract powder (8). They identified catechins in the plasma, 1 to 4 hours after the intake of tea, predominantly in conjugated (either glucuronide or sulfate) forms and in the concentration range of 50–300 na- nograms catechins/ml. The excretion of catechins in the urine was also predominantly in conjugated forms and began three hours after ingestion, then tended to level off after six hours. The cumulative amount of excreted catechins was only a few milligrams each as compared to the total amount of 235 mg catechins contained in the extract powder administered. Re- viewing all the above data in addition to our unpublished re- sults, it is thought to be very likely that tea catechins taken

FIG. 2 Structures of methylated (⫺)-epigallocatechin, (⫺)-epicatechin gal- late, and (⫺)-epigallocatechin gallate formed by a rat liver homogenate.

FIG. 3 Structures of (⫺)-epicatechin metabolites.

orally by humans will enter the small intestine and a part of them undergo conjugation in the process of absorption into the portal vein. In the liver, catechins undergo conjugations as well as methylations and a part of them is excreted into the bile, while the rest is excreted into urine. The majority of un- absorbed catechins travel to the large intestine and undergo certain degradation, entering the feces. Detailed studies of the distribution and elimination of tea catechins after oral intake are yet to be made. Using animals, this could be achieved by the use of labeled compounds. Stable, tritiated EGCg was pre- pared in the laboratory of Mitsui Norin Co., Ltd., in 1999, and its fate in rats is under detailed study. (Result to be pub- lished.)

REFERENCES

1. IC Shaw, LA Griffiths. Identification of the major biliary metab- olite of (⫹)-catechin in the rat. Xenobiotica 10:905–911, 1980.

2. M Wermeile, E Turin, LA Griffiths. Identification of the major urinary metabolites of (⫹)-catechin and 3-O-methyl-(⫹)-cate- chin in man. European J of Drug Metabolism and Pharmacoki- netics 8:77–84, 1983.

3. N Matsumoto, F Tono-oka, A Ishigaki, K Okushio, Y Hara. The fate of (⫺)-epigallocatechin gallate (EGCg) in the digestive tract of rats. Proceedings of the International Symposium on Tea Sci- ence, Shizuoka, Japan, 1991.

4. MR Meselhy, N Nakamura, M Hattori. Biotransformation of (⫺)-epicatechin 3-O-gallate by human intestinal bacteria. Chem Pharm Bull 45:888–893, 1997.

5. K Okushio, N Matsumoto, T Kohri, M Suzuki, F Nanjo, Y Hara. Absorption of tea catechins into rat portal vein. Biol Pharm Bull 19:326–329, 1996.

6. K Okushio, M Suzuki, N Matsumoto, F Nanjo, Y Hara. Methyla- tion of tea catechins by rat liver homogenates. Biosci Biotechnol Biochem 63:430–432, 1999.

7. K Okushio, M Suzuki, N Matsumoto, F Nanjo, Y Hara. Identifi- cation of (⫺)-epicatechin metabolites and their metabolic fate in the rat. Drug Metabolism and Disposition 27:309–316, 1999. 8. MJ Lee, ZY Wang, H Li, LS Chen, Y Sun, S Gobbo, DA Balan-

tine, CS Yang. Analysis of plasma and urinary tea polyphenols in human subjects. Can Epi, Biomarkers & Prev 4:393–399, 1995.

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