Hepatic and intestinal cytochrome P450 and conjugase activities in rats treated with black tea theafulvins and theaflavins F. Catterall, N.J. McArdle, L. Mitchell, A. Papayanni, M.N. Clifford, C. Ioannides* School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK Accepted 25 February 2003 Abstract Theaflavinsandtheafulvins,afractionofthearubigins,wereisolatedfromaqueousinfusionsofblacktea,andtheireffectsonthe hepatic and intestinal cytochrome P450 system, and on the glutathione S-transferase, epoxide hydrolase, glucuronosyl transferase and sulphotransferase enzyme systems were investigated in rats following oral intake for four weeks. Neither theafulvins nor thea- flavins influenced cytochrome P450 activity in the liver as exemplified by the O-dealkylations of methoxy-, ethoxy- and pentoxyr- esorufin, the hydroxylations of lauric acid and p-nitrophenol, and the N-demethylation of erythromycin; similarly, hepatic xenobiotic conjugation systems were unaffected. In the intestine, both polyphenolic fractions markedly suppressed the O-deethyla- tion of ethoxyresorufin and this was accompanied by a decrease in the CYP1A1 apoprotein levels. Probing intestinal microsomes with antibodies to CYP2E1 revealed the presence of a single band in the cytochrome P450 region whose intensity was lower in the polyphenol-treated animals. Immunoblot analysis utilising antibodies to CYP3A showed that the treatment with theafulvins and theaflavins reduced the apoprotein levels. A single band in the cytochrome P450 region was evident when the intestinal microsomes were probed with antibodies to CYP4A1 but the level of expression was not affected by the treatment with the black tea poly- phenols. Finally, treatment of the rats with theaflavins had no effect on any of the intestinal conjugating enzymes studied, but treatment with theafulvins led to inhibition of glucuronosyl transferase activity. # 2003 Elsevier Science Ltd. All rights reserved. Keywords: Tea; Theaflavins; Theafulvins; Polyphenols; Cytochrome P450 1. Introduction Tea, at concentrations similar to those consumed by humans, has been shown repeatedly to antagonise the carcinogenicity of chemicals in animal models, and consequently constitutes a promising chemopreventive agent in humans (Yang et al., 2002). Although most studies were carried out using green tea, black tea, one of the most popular beverages in the UK, has also been established as a potential anticarcinogen. It has sup- pressed the carcinogenicity of azoxymethane, nitrosa- mines and polycyclic aromatic hydrocarbons in rodents (Wang et al., 1992, 1994; Caderni et al., 2000). Animportantcharacteristicofteaisthatitimpairsall stages of carcinogenesis, and multiple mechanisms appear to be responsible (Yang et al., 2002). In the Ames test, black tea effectively decreased the mutagenic activity of structurally diverse chemical carcinogens (Bu-Abbas et al., 1996). A major mechanism through whichblackteamayexerciseitsanti-initiationactivityis by modulating the xenobiotic-metabolising enzyme sys- tems in such a way as to limit the availability of geno- toxic metabolites. Indeed, exposure of rats to black tea resulted in up-regulation of CYP1A2 and a selective increase in the Phase II enzyme systems glutathione S-transferases and UDPGA-glucuronosyl transferases (Sohn et al., 1994; Bu-Abbas et al., 1998, 1999). As a result of these effects, black tea alters the metabolism of carcinogens such as 2-amino-3-methylimidazo-[4,5- f]quinoline (IQ), leading to reduced excretion of muta- gens and promutagens in rats treated with a single oral dose of this carcinogen (McArdle et al., 1999). Caffeine appears to be the tea constituent responsible for the effect of black tea on the up-regulation of CYP1A2 (Chen et al., 1996; Bu-Abbas et al., 1999; McArdle et al., 1999). Metabolic studies have shown that in rats, 0278-6915/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0278-6915(03)00073-5 Food and Chemical Toxicology 41 (2003) 1141–1147 www.elsevier.com/locate/foodchemtox * Corresponding author. Tel.: +44-1483-259709; fax: +44-1483- 576978. E-mail address: c.ioannides@surrey.ac.uk (C. Ioannides).