6PP, a prenylated flavonoid from Dalea elegans, inhibits mitochondrial respiration and induces mitochondrial-dependent cytotoxic activity

CELENTANO AM, ISOLABELLA MP, ELINGOLD I, PEREZ C, CASANOVA MB, CABRERA JL, DIEZ RA, DUBIN M.

Buenos Aires

Jornada; VIII Jornadas Multisciplinarias de la Sociedad Argentina de Biología; 2006

Sociedad Argentina de Biología

6PP, A PRENYLATED FLAVONOID FROM Dalea elegans, INHIBITS MITOCHONDRIAL RESPIRATION AND INDUCES MITOCHONDRIAL-DEPENDENT CYTOTOXIC ACTIVITY. Celentano AM1, Isolabella MP2, Elingold I3, Pérez C4, Casanova MB3, Cabrera JL5,  Diez RA2, Dubin M3. Dptos. 1Microbiología y  2Farmacología, 3CEFYBO UBA-CONICET, Fac. Medicina, 4Cát.  Farmacología, Fac. Odontología (UBA) y 5Farmacognosia, Fac. Cs. Qcas. (UNC). E-mail: amcele@fmed.uba.ar.   The prenylated flavanone 2´-4´-dihidroxy-5´-(1´´´-dimethylallyl)-6-prenylpinocembrin (6PP), obtained from the roots of Dalea elegans, shows antimicrobial activity. Flavonoids depict multiple biological activities including antioxidant effects and/or impairment of mitochondrial function. The aim of our work was to evaluate mitochondrial toxicity of 6PP.  When evaluating oxidative phosphorylation system in rat liver mitochondria, 6PP (50, 100 μM) with malate-glutamate as substrate, stimulated O2 uptake in state 4 and inhibited it in state 3 (p<0.05). When succinate was the substrate, 6PP inhibited O2 uptake in state 4 at 100 μM (p<0.01) and inhibited it in state 3 at concentrations 12.5-100 μM (p<0.01). As a result, in both conditions respiratory control index  values decreased at 6PP concentrations 12.5-100 μM (p<0.01).  6PP inhibited F0F1 ATPase activity in coupled mitochondria (37.2±6.5%-50 mM; 51.0±3.3%-100 mM; both p<0.01) and in submitochondrial particles  (46.2±6.0% 100 mM; p<0.01). To assess cytotoxicity, MTT assay was employed. HEp-2 cells were incubated 24h with 6PP in presence or absence of  0.5% albumin. In the albumin-free group, 6PP was cytotoxic in a dose-dependent manner between 10 µM and 400 μM (p<0.01). Albumin decreased  6PP effect (inhibition of MTT reduction only at 200-400 μM, p<0.01), likely suggesting a lowered free fraction. We conclude that this flavanone affects mitochondrial respiratory chain and ATPase activity, inducing cytotoxic effects via mitochondrial damage. Further studies are needed to complete this evaluation.