Tea is rich in antioxidant polyphenols (catechins, flavonols, theaflavins and thearubigins). Epidemiological evidence relating regular consumption of tea or related polyphenols to CHD is equivocal. Catechins are absorbed from tea, but low plasma concentrations are attained. The bioavailability of theaflavins and thearubigins is unknown. Tea does not reduce blood pressure or plasma lipids in well-controlled human trials. Tea polyphenols inhibit LDL lipid peroxidation in vitro, but the effect ex vivo is small. The plasma antioxidant potential increases after drinking green but not black tea. Tea consumption tended to reduce the development of aortic atherosclerosis in rabbits. Tea polyphenols exert marked effects on cells, and inhibit neutrophil migration and inflammatory responses, sometimes at low concentrations. These diverging results suggest potential beneficial effects, but emphasize the need for good human trials of tea using early markers of CHD before firm conclusions can be drawn.

There is considerable current interest in the cytoprotective effects of natural antioxidants against oxidative stress. In particular, epicatechin, a major member of the flavanol family of polyphenols with powerful antioxidant properties in vitro, has been investigated to determine its ability to attenuate oxidative-stress-induced cell damage and to understand the mechanism of its protective action. We have induced oxidative stress in cultured human fibroblasts using hydrogen peroxide and examined the cellular responses in the form of mitochondrial function, cell-membrane damage, annexin-V binding and caspase-3 activation. Since one of the major metabolites of epicatechin in vivo is 3'-O-methyl epicatechin, we have compared its protective effects with that of epicatechin. The results provide the first evidence that 3'-O-methyl epicatechin inhibits cell death induced by hydrogen peroxide and that the mechanism involves suppression of caspase-3 activity as a marker for apoptosis. Furthermore, the protection elicited by 3'-O-methyl epicatechin is not significantly different from that of epicatechin, suggesting that hydrogen-donating antioxidant activity is not the primary mechanism of protection.

Hydrogen peroxide is an oxidizing agent which can be generated intracellularly either during normal metabolism or by treatment with external agents including solar UV radiation. Simian cells (CV-1) transfected with the SV40-based shuttle vector plasmid pZ189 have been treated with H 2 O 2 and then incubated to allow repair and replication of the plasmid. The frequency of mutations at the supF locus of the recovered plasmid increases by a factor of up to four over the spontaneous value. The nucleotide changes associated with 100 spontaneous and 100 H 2 O 2 -induced mutants have been determined directly by sequencing a 150 bp fragment that includes the entire supF tRNA coding region. Deletions were observed in -45% of both the spontaneous and induced mutants, whereas single or multiple base changes arose in 68 and 57% of the induced and spontaneous mutants respectively. The spectrum of induced mutations is characterized by (i) the occurrence of deletions associated with base changes (16% of all mutants analysed) and (ii) small deletions of 3 bp and less (51% of all deletion mutants sequenced). Sixty-five per cent (15 out of 23) of all small deletions (spontaneous and induced) are associated with runs of between two and five identical bases and eight of them arise at a mutational 'hotspot' region of five cytosines between bp 172 and 176. The majority (19 out of 30) of completely sequenced deletions observed in the spontaneous spectrum contain either (i) small (2-10 bp) direct repeat sequences that lie immediately outside one deletion terminus and immediately inside the second deletion terminus or (ii) small (2-3 bp) inverted repeat sequences lying immediately inside the two deletion termini. Most deletions that we have observed are therefore likely to arise as a consequence of specific aspects of DNA structure. IntroductionOxygen radicals appear to be involved in both the ageing process and in the initiation and progression of many human diseases, including cancer. A knowledge of the nature of mutations arising in DNA as a result of oxygen radical attack should provide important clues to understanding the molecular events that underlie these pathological changes. The characterization of the genotoxic action of the oxidizing agent, hydrogen peroxide, is particularly relevant in this respect for several reasons. In addition

The pharmacodynamic effects of metronidazole on Trichomonas vaginalis have been poorly characterized. The present in vitro study was performed to characterize the relationship between killing of trichomonads and metronidazole exposure (metronidazole concentration and time of exposure). Five laboratory strains and five recent clinical isolates of T. vaginalis were studied. The minimum lethal concentrations (MLCs) of metronidazole for the strains ranged from 0.8 to 25 g/ml under anaerobic conditions. Metronidazole exhibited concentration-dependent killing against T. vaginalis at concentrations ranging from 0.1 to >10 times the MLC. The endpoint measurement, the kill rate constant, which was derived from the reduction in the logarithm of the colony count divided by exposure time, compared with the kill rate constant for the growth control was not affected by the time of assessment between 2 and 24 h. The kill rate constant-versus-metronidazole exposure curves were similar when concentration was expressed as a multiple of the MLC. There were no apparent differences between the clinical isolates and laboratory strains. These data suggest that peak metronidazole concentration and/or area under the plasma concentration-versus-time curve are the important pharmacodynamic parameters to be optimized.Metronidazole is the treatment of choice for genitourinary infections caused by Trichomonas vaginalis, but it is also used in the treatment of amebiasis, giardiasis, and anaerobic bacterial infections (7). Overall, a large number of different dosing regimens have been used in clinical trials resulting in cure rates of between 55 and 100% (4). Dosing regimens vary from the 1-to 2-g single-dose regimens to the regimens that use 600 to 1,000 mg as divided doses daily for 3 to 10 days. Yet, all regimens appear to have similar efficacies. Metronidazole appears to be equally effective against T. vaginalis when it is administered orally as a single 2-g dose or as a 7-day regimen of 250 mg three times daily (5). The single oral dose provides advantages in terms of compliance; however, the 7-day regimens minimize the occurrences of reinfection while sexual contacts are being treated (6, 11). A 2-g total dose given once is equal in efficacy to 5.25 g (250 mg three times a day for 7 days). However, a 1-g single dose is less effective for the treatment of Trichomonas vaginitis. This suggests that either a high peak concentration or area under the plasma concentrationtime curve is the important pharmacodynamic property for optimizing the activity of metronidazole. The study described here was performed to investigate the relationship between killing of T. vaginalis and the concentration of metronidazole.No official methods have been adopted by the National Committee for Clinical Laboratory Standards for testing the susceptibility of T. vaginalis; however, an assay introduced by Meingassner et al. (8) for Tritrichomonas foetus that was subsequently applied to T. vaginalis (9, 10) appears to differentiate clinically resistant strains from t...

The effects of novobiocin and nalidixic acid on the specific toxicity of aphidicolin towards u.v. irradiated arrested (nondividing) human skin fibroblasts have been determined. Contrary to the result expected if either drug were causing inhibition of excision repair at a pre-incision step the sector of toxicity due to a combined treatment of 300 micrograms ml-1 nalidixic acid and 1.0 micrograms ml-1 aphidicolin is unchanged when compared with that due to treatment with 1.0 micrograms ml-1 aphidicolin alone, while that for 150 micrograms ml-1 novobiocin + 1.0 micrograms ml-1 aphidicolin was slightly increased. In parallel measurements of the inhibition of u.v.-induced DNA repair synthesis in arrested fibroblasts by these drugs, 150 micrograms ml-1 novobiocin inhibited repair synthesis by approximately 60% over the fluence range employed. Nalidixic acid at a concentration of 300 micrograms ml-1 caused no detectable inhibition of repair synthesis. We conclude that the mode of action of novobiocin in the inhibition of DNA excision repair is not via the inhibition of a pre-incision step and the data do not support the hypothesis that a type II topoisomerase mediated change in DNA supercoiling is an essential early step in excision repair of u.v.-induced damage.

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