Evaluation of Cytotoxic, Genotoxic and CYP450 Enzymatic Competition Effects of Tanzanian Plant Extracts Traditionally Used for Treatment of Fungal Infections

Abstract

HIV-infected patients in sub-Saharan countries highly depend on traditional medicines for the treatment of opportunistic oral infections as candidiasis. Previous investigations on antifungal activity of medicinal plant extracts utilized by traditional healers in Tanzania have revealed 12 extracts with potent antifungal activity. Although the plants may be good candidates for new treatment opportunities, they can be toxic or genotoxic and could cause pharmacokinetic interactions when used concomitantly with antiretroviral agents. Therefore, we investigated the cytotoxicity, genotoxicity and cytochrome P450 interaction potential of these medicinal plants. Cytotoxicity was tested by Hoechst 33342, Alamar Blue, calcein-AM, glutathione depletion and O 2 -consumption assays and genotoxicity by a Vitotox assay. Competition of the 12 extracts on substrate metabolism by CYP3A4, 2C9, 2C19 and 2D6 was tested with high-throughput CYP inhibition screening. Pregnane X receptor (PXR) activation was tested using Chinese hamster ovary cell lines expressing human PXR. Herbal extracts inducing high human PXR activation were tested for enhanced CYP3A4 mRNA levels with quantitative polymerase chain reaction. Genotoxicity was found for Jatropha multifida , Sterculia africana and Spirostachys africana . All plant extracts showed high cytotoxic effects in almost all tests. Potent competition with CYP3A4, 2D6, 2C9 and 2C19 was found for 75% of the herbal extracts. Spirostachys africana did not affect CYP2D6 and for S. africana and Turraea holstii no effect on CYP2D6 and CYP3A4 (DBF) was found. Nine plant extracts showed significant activation of human PXR, but only Agaura salicifolia , Turraea holstii and S. africana significantly induced CYP3A4 mRNA levels. These results indicate the possibility of potential medicinal plant-antiretroviral interactions.Traditional medicines are commonly used in sub-Saharan countries like Tanzania, with up to 80% of the population depending on traditional medicines for their primary health care [1]. In Tanzania, up to 21% of the people who seeked care from public health care facilities first consult a traditional healer [2]. Especially, HIV-infected persons who often encounter opportunistic infections during their disease course highly depend on this form of health care. According to Medicine du Monde , a French non-governmental organization, in Kagera region, five out of every six HIV-infected patients receive their medical attention from a traditional healer rather than from a hospital or primary health care facility [3]. A survey among 532 HIV patients visiting the HIV clinic of Muhimbili National Hospital, Dar es Salaam, Tanzania, reported use of traditional medicines by 62 patients (11.7%). Focusing on HIV patients with oral lesions, mostly oral Candida infections, a prevalence of traditional medicine use of 40.3% was found [4].Fungal infections, like oral candidiasis, are commonly seen among HIV-infected patients in sub-Saharan Africa. The problems with effective management of these infec...

Drug interactions in African herbal remedies

“…The plants described below are included due to their effects on P-glycoprotein and CYP enzymes which could lead to possible drug-herb interactivity. (19) .…”

Ptaquiloside-induced cytotoxicity in Crandall feline kidney and HGC-27 cells

“…van den Bout-van den Beukel et al (26) investigated the cytotoxic, genotoxic and cytochrome P450 (CYP) enzymatic competition effects of Tanzanian plant extracts traditionally administered for the treatment of fungal infections, including Pteridium aquilinum . Methanolic extracts were applied to HepG2 and HeLa cells and the mitochondrial activity, cellular proliferation, damage to the cellular membrane, glutathione depletion and electron transport chain activity were investigated using Alamar Blue, Hoechst 33342, calcein-AM uptake, glutathione depletion and O 2 -consumption assays.…”

Could the products of Indian medicinal plants be the next alternative for the treatment of infections?

“…Certain plant products have been used to treat oral candidiasis. van den Bout-van den Beukel et al [8] investigated the cytotoxicity, genotoxicity and cytochrome P450 interaction potential of these medicinal plants. The researchers used Hoechst 33342 dye, Alamar Blue, calcein-AM, glutathione depletion and O 2 -consumption assays for cytotoxicity assay and Vitotox assay for genotoxicity testing.…”