Dissertation (PhD)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: This thesis provides the first scientific evidence on the cancer modulating properties of two unique South African herbal teas, rooibos (Aspalathus Iinearis) and honeybush (Cyclopia intermedia) utilizing in vitro as well as in vivo carcinogenesis assays by: • Demonstrating the in vitro antimutagenic activity of aqueous extracts of the herbal teas against the metabolic activated mutagens, 2-acetylaminofluorene (2- AAF) and the mycotoxin, aflatoxin B1 (AFB,) as well as, to a certain extent, against the direct acting mutagen, hydrogen peroxide, utilizing the Salmonella typhimurium mutagenicity assay. • Increasing the activity of hepatic drug metabolizing enzymes, glutathione Stransferase alpha and UPD-glucuronosyl transferase, and reduced the oxidative stress by stabilizing the level of reduced glutathione (GSH) resulting in an increased hepatic reduced to oxidized glutathione ratio (GSG:GSSG). No toxic effects were noticed in rats consuming the herbal teas for 10 weeks as their sole source of drinking fluid. • Demonstrating the ex vivo modulation of 2-AAF- and AFB1-induced mutagenesis by sub- cellular hepatic fractions of rats consuming the herbal teas in the Salmonella mutagenicity assay. Hepatic cytosolic fractions protected against mutagenesis of both mutagens, while the microsomal fractions exhibited a reduced capacity to metabolize AFB1 to its active mutagenic metabolite. • Providing evidence for the in vivo modulation of tumour promotion using the liver as well as the two-stage skin carcinogenesis animal models. The unprocessed herbal teas arrested proliferation of the placental form of glutathione-Stransferase (GSTP+) altered cells as well as reduced the total number of enzyme altered foci in the liver of rats. Topical application of polyphenolic fractions of the various herbal teas prior to 12-0-tetra-decanoylphorbol-13-acetate (TPA) tumour promotion, reduced tumour formation in mouse skin initiated with 7,12-dimethylbenz[ ajanthracene (DMBA). The protective effect was illustrated by a decreased tumour incidence, a reduction in tumour volume as well as a delayed onset of tumour development. The f1avanol/proanthocyanidin content of the fractions could playa major role in the protection against skin tumour promotion. • Proposing possible mechanisms whereby rooibos and honeybush herbal teas could exert their cancer modulating properties with respect to in vitro and ex vivo antimutagenicity, in vivo oxidative status and reduced tumour promotion. • Providing evidence that the herbal teas mimic the cancer modulating properties of green and black teas although differences exist, presumably due to differences in the polyphenolic constituents. • Suggesting that rooibos and honeybush herbal teas may play an important role as chemopreventive agents in the modulation of cancer. / AFRIKAANSE OPSOMMING: Hierdie tesis bevat die eerste ondersoek na die effek van waterige en polifenoliese ekstrakte van rooibos (Aspalathus Iinearis) en heuningbos (Cyclopia intermedia) op verskeie aspekte van kankerontwikkeling. Die twee kruietees is uniek aan Suid-Afrika en kan 'n belangrike rol speel in die voorkoming van kanker. Verskillende in vitro so wei as in vivo studies het die volgende getoon: • Antimutageniese aktiwiteite teen die metabolies-geaktiveerde mutagene, 2- asetielaminofluoreen (2-AAF) en die mikotoksien, aflatoksien B1 (AFB1) in die Salmonella fyphimurium mutagenisiteitstoets. 'n Beperkte mate van beskerming is ook verleen teen die oksidatiewe mutageen, waterstofperoksied, sonder metaboliese aktivering. • Verhoogde aktiwiteite van die fase II ensieme, glutatioon S-tranferase alfa en UDP-glukuronidase, wat liggaamsvreemde verbindings metaboliseer. Die kruietees verlaag die oksidasietoestand soos weerspieel word deur 'n toename van gereduseerde glutatioon tot die geoksideerde vorm in die lewer van rotte wat 10 weke hierdie kruietees gedrink he!. Die kruietees het geen toksiese uitwerking op die rotte gehad nie. • Antimutageniese aktiwiteite van subselluiE~re fraksies van die lewer teenoor 2- AAF en AFB1 in die Salmonella toets. Die sitosolfraksie van die rotlewer bied beskerming teen die ge"induseerde mutagenese van beide mutagene, terwyl die mikrosomale fraksie ook die metaboliese aktivering van AFB1 na die aktiewe mutageniese metaboliet verminder. • In vivo modulering van kankerpromosie met behulp van bekende rotlewer en muisvel kankerontwikkelingsmodelle. In die lewermodel het die ongeprosesseerde kruietees beide die ontwikkeling en getal van GSTP+ fokusse onderskeidelik vertraag en verminder. In die geval van die velkankermodel het aanwending van polifenoliese fraksies van die kruietees beskerming gebied teen die ontwikkeling van velkankers by muise. Die aantal en grootte van die tumors het afgeneem terwyl die verskyning daarvan ook vertraag is. • Verskeie meganismes waardeur rooibos- en heuningboslee moonllik kanker kan moduleer word voorgeslel. Verskille in die polifenoliese sameslelling asook hul onderskeie konsenlrasies kan 'n belangrike rol speel in die kankerveranderende effekle van die lees. • Oal gereelde inname van rooibos- en/of heuningboslee moonllik 'n belangrike rol kan speel in die voorkoming van dieel- en omgewings-geYnduseerde kankers.