Peter Kovacic

Mechanism of mitochondrial uncouplers, inhibitors, and toxins : Focus on electron transfer, free radicals, and structure-activity relationships

The biology of the mitochondrial electron transport chain is summarized. Our approach to the mechanism of uncouplers, inhibitors, and toxins is based on electron transfer (ET) and reactive oxygen species (ROS). Extensive supporting evidence, which is broadly applicable, is cited. ROS can be generated either endogenously or exogenously. Generally, the reactive entities arise via redox cycling by ET functionalities, such as, quinones (or precursors), metal compounds, imines (or iminiums), and aromatic nitro compounds (or reduced metabolites). In most cases, the ET functions are formed metabolically. The toxic substances belong to many categories, e.g., medicinals, industrial chemicals, abused drugs, and pesticides. Structure-activity relationships are presented from the ET-ROS perspective, and also quantitatively. Evidence for the theoretical framework is provided by the protective effect of antioxidants. Among other topics addressed are proton flux, membrane pores, and apoptosis. There is support for the thesis that mitochondrial insult may contribute to illnesses and aging.

Nitroaromatic compounds: Environmental toxicity, carcinogenicity, mutagenicity, therapy and mechanism.

Vehicle pollution is an increasing problem in the industrial world. Aromatic nitro compounds comprise a significant portion of the threat. In this review, the class includes nitro derivatives of benzene, biphenyls, naphthalenes, benzanthrone and polycyclic aromatic hydrocarbons, plus nitroheteroaromatic compounds. The numerous toxic manifestations are discussed. An appreciable number of drugs incorporate the nitroaromatic structure. The mechanistic aspects of both toxicity and therapy are addressed in the context of a unifying mechanism involving electron transfer, reactive oxygen species, oxidative stress and antioxidants. Copyright

Multifaceted Approach to Resveratrol Bioactivity: Focus on Antioxidant Action, Cell Signaling and Safety

Resveratrol (RVT) is a naturally occurring trihydroxy stilbene that displays a wide spectrum of physiological activity. Its ability to behave therapeutically as a component of red wine has attracted wide attention. The phenol acts as a protective agent involving various body constituents. Most attention has been given to beneficial effects in insults involving cancer, aging, cardiovascular system, inflammation and the central nervous system. One of the principal modes of action appears to be as antioxidant. Other mechanistic pathways entail cell signaling, apoptosis and gene expression. There is an intriguing dichotomy in relation to pro-oxidant property. Also discussed are metabolism, receptor binding, rationale for safety and suggestions for future work. This is the first comprehensive review of RVT based on a broad, unifying mechanism.

How safe is bisphenol A? Fundamentals of toxicity: Metabolism, electron transfer and oxidative stress

The FDA recently announced concern about the safety of bisphenol A (BPA) and the need for more research. In the current controversy, scant attention is being paid to toxicity at the fundamental, molecular level, which is the topic of this report. Important information is provided by extensive studies on metabolism. The principal pathway is detoxification, mainly by conjugation leading to a glucuronide. A minor route entails oxidation by hydroxylation to a catechol followed by further transformation to an o-quinone. The catechol-o-quinone couple is capable of redox cycling with generation of reactive oxygen species (ROS) and oxidative stress (OS). o-Quinones are highly electron affinic with very favorable reduction potentials that permit electron transfer (ET) under physiological conditions. Only small amounts are sufficient to generate large quantities of ROS catalytically. There is extensive evidence for production of ROS, which buttresses ET by o-quinone as a plausible source. In addition, there are numerous reports on toxicity to body constituents by BPA. Those adversely affected include the liver, DNA, genes, CNS, reproductive system and kidney. Since a plethora of prior studies links ROS-OS with toxicity, it is reasonable to propose a similar connection for BPA. Cell signaling also plays a role. There are various other factors involved with toxic responses, including age, with the fetus and infants being the most vulnerable. A report concludes that human exposure to BPA is not negligible. The present overview represents a novel, integrated approach to BPA toxicity. A similar article was recently published in this journal which deals with toxicity of prevalent phthalate plasticizers.

Electromagnetic fields: mechanism, cell signaling, other bioprocesses, toxicity, radicals, antioxidants and beneficial effects

Electromagnetic fields (EMFs) played a role in the initiation of living systems, as well as subsequent evolution. The more recent literature on electrochemistry is documented, as well as magnetism. The large numbers of reports on interaction with living systems and the consequences are presented. An important aspect is involvement with cell signaling and resultant effects in which numerous signaling pathways participate. Much research has been devoted to the influence of man-made EMFs, e.g., from cell phones and electrical lines, on human health. The degree of seriousness is unresolved at present. The relationship of EMFs to reactive oxygen species (ROS) and oxidative stress (OS) is discussed. There is evidence that indicates a relationship involving EMFs, ROS, and OS with toxic effects. Various articles deal with the beneficial aspects of antioxidants (AOs) in countering the harmful influence from ROS-OS associated with EMFs. EMFs are useful in medicine, as indicated by healing bone fractures. Beneficial effects are recorded from electrical treatment of patients with Parkinson’s disease, depression, and cancer.

Integrated Approach to Immunotoxicity: Electron Transfer, Reactive Oxygen Species, Antioxidants, Cell Signaling, and Receptors

As with all body organs, the immune system is subjected to attack by a variety of toxins. Serious consequences can result because the immune organs serve as a defense against infective agents. The toxins, both organic and inorganic, fall into a large variety of classes, such as metals, therapeutic drugs, industrial chemicals, pollutants, pesticides, fuels, herbicides and abused drugs. Although the mode of action is multifaceted, our focus is on electron transfer (ET), reactive oxygen species (ROS), antioxidants (AOs), cell signaling, and receptors. It is significant that the toxins or their metabolites incorporate ET functionalities capable of redox cycling with resultant generation of ROS and accompanying oxidative stress.

Pulmonary Toxicity and Environmental Contamination: Radicals, Electron Transfer, and Protection by Antioxidants

The atmosphere is replete with a mixture of toxic substances, both natural and man-made. Inhalation of toxic substances produces a variety of insults to the pulmonary system. Lung poisons include industrial materials, particulates from mining and combustion, agricultural chemicals, cigarette smoke, ozone, and nitrogen oxides, among a large number of other chemicals and environmental contaminants. Many proposals have been advanced to explain the mode of action of pulmonary toxicants. In this review we focus on mechanisms of pulmonary toxicity that involve ET, ROS, and OS. The vast majority of toxicants or their metabolites possess chemical ET functionalities that can undergo redox cycling. Such recycling may generate ROS that can injure various cellular constituents in the lung and in other tissues. ET agents include quinones, metal complexes, aromatic nitro compounds, and conjugated iminium ions. Often, these agents are formed metabolically from parent toxicants. Such metabolic reactions are often catalytic and require only small amounts of the offending material. Oxidative attack is commonly associated with lipid peroxidation and oxidation of DNA, and it may result in strand cleavage and 8-OH-DG production. Toxicity is often accompanied by depletion of natural AOs, which further exacerbates the toxic effect. It is not surprising that the use of AOs, both natural in fruits and vegetables, as well as synthetic, may provide protection from the adverse effects of toxicant exposure. The mechanistic framework described earlier is also applicable to some of the more prominent pulmonary illnesses, such as asthma, COPD, and cancer.

Hydroxyurea (therapeutics and mechanism): Metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications

During a century, hydroxyurea has received much attention in relation to its physiological properties. This review mainly deals with the metabolism, mechanism, cell signaling, therapeutic properties, bioactivity, receptors, and toxicity. Metabolism provides insight concerning the mechanism. Carbamoyl nitroso is an intermediate, based on ease of oxidation of the parent and subsequent formation of nitroxyl and nitric oxide. Carbamoyl nitroso bears structural and electrochemical similarity to acyl nitroso from hydroxamic acids, to the phenylhydroxylamine-nitrosobenzene couple, and to α-dicarbonyls. Carbamoyl nitroso may be involved in electron transfer, reactive oxygen species formation, and oxidative stress. Cell signaling plays a significant role in the biological action. The therapeutic properties are discussed with emphasis on cancer, sickle cell disease, HIV, skin, and genes. Promise as a practical medicine is indicated by clinical trials. Toxicity is also included. Carbamoyl nitroso, nitroxyl, nitric oxide, and metal complexes of the parent drug are designated the main actors in the physiological effects. The mechanistic theme is in keeping with prior reports in Medical Hypotheses.

Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity.

Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3′-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and anti-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties.

Role of diacetyl metabolite in alcohol toxicity and addiction via electron transfer and oxidative stress

There are many gaps in our knowledge of the molecular basis of alcohol toxicity and addiction. Metabolism affords mainly acetic acid via acetaldehyde. A minor metabolite, diacetyl (an α-dicarbonyl), arises from the aldehyde. We propose that this C4 entity and/or its iminium derivatives from condensation with protein amino groups plays important roles in bioresponses. A review of the literature reveals substantial support for this premise. Reduction potentials for diacetyl and its iminium derivatives fall in the range favorable for catalytic electron transfer in vivo, which can generate oxidative stress via reactive oxygen species due to redox cycling. Oxidative stress and reactive oxygen species are linked to toxicity associated with major organs by alcohol. The α-dicarbonyl moiety in related substances is believed to induce various toxic responses, such as Alzheimer’s disease, mutagenesis, and carcinogenesis. In addition to discussion of addiction and computational studies, potential applications for health improvement are suggested.