Mitochondrial toxicity and antioxidant activity of a prenylated flavonoid isolated from Dalea elegans

• DOI: 10.1016/j.cbi.2007.10.005
• Publication Date: 2007-10-26T09:58:26Z
• Authors: Igal Elingold; M. Paula Isollabella; Marta B. Casanova; Ana M. Celentano; Cristina Pérez; José Luis Cabrera; Roberto A. Diez; Marta Dubin
• Keywords: Male; 0301 basic medicine; Cell Survival; Antineoplastic Agents; Mitochondria, Liver; MITOCHONDRIAL; TOXICITY; Antioxidants; FLAVONOID; 03 medical and health sciences; Multienzyme Complexes; ANTIOXIDANT; https://purl.org/becyt/ford/1.6; Animals; Humans; NADH, NADPH Oxidoreductases; Enzyme Inhibitors; https://purl.org/becyt/ford/1; Flavonoids; Dose-Response Relationship, Drug; Molecular Structure; Fabaceae; Enzyme Activation; Oxygen; Flavanones; Mitochondrial Membranes; Lipid Peroxidation; Drug Screening Assays, Antitumor

The prenylated flavanone 2'-4'-dihidroxy-5'-(1" '-dimethylallyl)-6-prenylpinocembrin) (6PP), isolated from the roots of Dalea elegans, shows antimicrobial activity. The aim of this study was to evaluate mitochondrial toxicity and antioxidant properties of 6PP. Addition of micromolar concentrations of 6PP to rat liver mitochondria, stimulated O2 uptake in state 4 and inhibited it in state 3 when malate-glutamate was the respiratory substrate, and inhibited O2 uptake in state 3 when succinate was the substrate. Highest concentration of 6PP also inhibited O2 uptake in state 4 in the latter case; in both conditions, respiratory control index values were decreased. This flavanone collapsed the mitochondrial membrane potential in a concentration-dependent manner. 6PP also inhibited F0F1-ATPase activity in coupled mitochondria and in submitochondrial particles. In the latter, this compound also inhibited NADH oxidase and succinate dehydrogenase activities. HEp-2 cells were incubated for 24 h with 6PP in presence or absence of 0.5% albumin. As measured by reduction of the mitochondrial-related probe MTT, in the albumin-free condition, 6PP was cytotoxic in a concentration-dependent manner; on the other hand, albumin decreased 6PP effect. In addition, in rat liver microsomes 6PP: (1) inhibited the enzymatic lipid peroxidation, (2) exhibited significant scavenging activity, measured by DPPH reduction assay and (3) demonstrated significant antioxidant activity by decreasing the reduction of Mo(VI) to Mo(V). We suggest that 6PP impairs the hepatic energy metabolism by acting as mitochondrial uncoupler and by inhibiting enzymatic activities linked to the respiratory chain. 6PP also exerts both antioxidant and antiradical activities. Due to its cytotoxicity, this molecule, and its future structure developments, can be considered as a potentially promising therapeutic agent, for instance in cancer chemotherapy.