Evaluation of cytotoxic, genotoxic and CYP450 enzymatic competition effects of Tanzanian plant extracts traditionally used for treatment of fungal infections.
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.
van den Bout-van den Beukel
Carolien J P
CJ
Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. c.vandenbeukel@aig.umcn.nl
Hamza
Omar J M
OJ
Moshi
Mainen J
MJ
Matee
Mecky I N
MI
Mikx
Frans
F
Burger
David M
DM
Koopmans
Peter P
PP
Verweij
Paul E
PE
Schoonen
Willem G E J
WG
van der Ven
André J A M
AJ
D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004269:DNA, Bacterial / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D020834:Ethnopharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005798:Genes, Bacterial / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D016488:Medicine, African Traditional; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D010936:Plant Extracts / Q000378:metabolism / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D000077297:Pregnane X Receptor; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism; D013636:Tanzania
D000935:Antifungal Agents; D004269:DNA, Bacterial; D009153:Mutagens; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System