Prevention of drug-induced programmed and unprogrammed cell death by citrus flavonoids

Cell life and cell death in vivo are delicately balanced and linked processes dependent upon several "death" or "survival" signals from inside and outside the cell. These signals are regulated by several vital intracellular events associated with DNA, RNA, caspases, proteins, and ions. Drugs and other chemicals are known to threaten the stability of such key intracellular molecules by causing ion deregulation, oxidative stress, DNA fragmentation and activation of caspases. Citrus flavonoids, such as hesperidin (HES) and rutin (RUT), are known to specifically interfere with such deleterious pathways, minimize macromolecular perturbations, and exhibit their prolific antitoxic properties. This study was designed to investigate whether HES and RUT pre-exposures (1.25g/kg orally for 14 days) have the ability to counteract hepatotoxicity and nephrotoxicity induced by toxic doses of acetaminophen (APAP, 500 mg/kg, ip) and diclofenac (DCLF, 200 mg/kg, po) respectively in vivo. Additional objectives were to determine whether exposure to these flavonoids protect the liver and kidneys from oxidative stress and genomic DNA fragmentation, the prime players responsible for turning on various forms of cell death. Results indicate that HES and RUT pre-exposures showed dramatic prevention of hepato- and nephrotoxicity by minimizing toxicant-induced oxidative stress and genomic DNA fragmentation which are instrumental in orchestrating apoptotic (programmed) and necrotic (unprogrammed) cell deaths in these organs in vivo.