title: Oxidative stress is the master operator of drug and chemically-induced programmed and unprogrammed cell death: Implications of natural antioxidants in vivo.
abstract: ROS, RNS, BRIs and ROS-RNS hybrids are produced during drug or chemical metabolism in vivo. These reactive species are instrumental to the culmination of cellular oxidative stress (OS). OS, once turned on, does not spare any vital intracellular macromolecule, such as glutathione, DNA, RNA, proteins, enzymes, lipids and ATP. Since concentration gradients of such components are very delicately balanced for normal cellular functioning, a gross perturbation leads to cell injury and cell death. Abundant evidence now suggests that intracellular antioxidants keep OS in check and maintain homeostasis. Our laboratory has focused on the role of OS in orchestrating various forms of cell death during drug and chemically-induced target organ toxicity and their counteraction by various natural or synthetic antioxidants in in vivo models. Despite complexity of the in vivo models, results show that metabolism of xenobiotics are invariably associated with different degrees of OS and natural antioxidants such as grape seed extract, bitter melon extract (Momordica charantia) and N-acetylcysteine (NAC) which were very effective in counteracting organ toxicities by minimizing events linked to OS (lipid peroxidation and total glutathione), and CAD-mediated DNA fragmentation. Phytoextract exposure rescued cells from toxic assaults, protected genomic integrity, and minimized apoptotic, necrotic and apocrotic (oncotic necrosis) cell deaths. Pre-exposure mode was more effective than post-exposure route. Overall scenario suggests that OS may have been the prime modulator of death and/or survival programs, whereas, antioxidants may have imparted a dual role in either erasing death signals or reviving survival signals, and a combination of antioxidants may be more beneficial than a single entity to influence a number of intracellular events operating simultaneously to neutralize chaotic toxicological consequences.
authors.affiliation: Molecular Toxicology Program, Department of Pharmacology, Toxicology & Medicinal Chemistry, Arnold and Marie Schwartz College of Pharmacy & Health Sciences, Long Island University, Brooklyn, NY 11201, USA. sray@liu.edu
authors.forename: S D
authors.initials: SD
authors.lastname: Ray
authors.forename: T S
authors.initials: TS
authors.lastname: Lam
authors.forename: J A
authors.initials: JA
authors.lastname: Rotollo
authors.forename: S
authors.initials: S
authors.lastname: Phadke
authors.forename: C
authors.initials: C
authors.lastname: Patel
authors.forename: A
authors.initials: A
authors.lastname: Dontabhaktuni
authors.forename: S
authors.initials: S
authors.lastname: Mohammad
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Strika
authors.forename: A
authors.initials: A
authors.lastname: Dobrogowska
authors.forename: C
authors.initials: C
authors.lastname: Bruculeri
authors.forename: A
authors.initials: A
authors.lastname: Chou
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.forename: T
authors.initials: T
authors.lastname: Manolas
authors.forename: S
authors.initials: S
authors.lastname: Stohs
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D005665:Furosemide / Q000008:administration & dosage / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000502:physiology*; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D005665:Furosemide